Publications by authors named "Ryusho Kariya"

53 Publications

A Therapeutic Strategy to Combat HIV-1 Latently Infected Cells With a Combination of Latency-Reversing Agents Containing DAG-Lactone PKC Activators.

Front Microbiol 2021 17;12:636276. Epub 2021 Mar 17.

National Center for Global Health and Medicine Research Institute, Tokyo, Japan.

Advances in antiviral therapy have dramatically improved the therapeutic effects on HIV type 1 (HIV-1) infection. However, even with potent combined antiretroviral therapy, HIV-1 latently infected cells cannot be fully eradicated. Latency-reversing agents (LRAs) are considered a potential tool for eliminating such cells; however, recent and studies have raised serious concerns regarding the efficacy and safety of the "shock and kill" strategy using LRAs. In the present study, we examined the activity and safety of a panel of protein kinase C (PKC) activators with a diacylglycerol (DAG)-lactone structure that mimics DAG, an endogenous ligand for PKC isozymes. YSE028, a DAG-lactone derivative, reversed HIV-1 latency when tested using HIV-1 latently infected cells (e.g., ACH2 and J-Lat cells) and primary cells from HIV-1-infected individuals. The activity of YSE028 in reversing HIV-1 latency was synergistically enhanced when combined with JQ1, a bromodomain and extra-terminal inhibitor LRA. DAG-lactone PKC activators also induced caspase-mediated apoptosis, specifically in HIV-1 latently infected cells. In addition, these DAG-lactone PKC activators showed minimal toxicity and . These data suggest that DAG-lactone PKC activators may serve as potential candidates for combination therapy against HIV-1 latently infected cells, especially when combined with other LRAs with a different mechanism, to minimize side effects and achieve maximum efficacy in various reservoir cells of the whole body.
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http://dx.doi.org/10.3389/fmicb.2021.636276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010149PMC
March 2021

Cucurbitacin B induces apoptosis of primary effusion lymphoma via disruption of cytoskeletal organization.

Phytomedicine 2021 Mar 10;85:153545. Epub 2021 Mar 10.

Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan; Division of Hematopoiesis, Graduate School of Medical Sciences, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan. Electronic address:

Background: Primary effusion lymphoma (PEL) is an aggressive B cell non-Hodgkin lymphoma that develops especially in AIDS patients and immunocompromised patients infected with human herpes virus-8 (HHV-8)/Kaposi's sarcoma-associated herpesvirus (KSHV). PEL has a poor prognosis in patients despite conventional chemotherapeutic treatment, and a safe and efficient therapy is required.

Purpose: To examine the effects on PEL of cucurbitacin B (CuB), a triterpene found in plants of the Cucurbitaceae family that has several anti-cancer activities.

Study Design: We evaluated the anti-cancer activities of CuB in vitro and in vivo.

Methods: Cell proliferation of PEL cell lines was measured by MTT assay. Cleaved caspases and signaling transduction associated proteins were analyzed by western blotting. Wright and Giemsa staining and immunofluorescence staining were carried out to observe cell morphology. Cell cycles were analyzed by flow cytometry. RT-PCR was performed to detect viral gene expressions. A xenograft mouse model was employed to evaluate the anti-cancer activity of CuB in vivo.

Results: CuB inhibited cell proliferation of PEL cell lines (BCBL-1, BC-1, GTO and TY-1) in a dose-dependent manner (0-50 nM) and induced apoptosis of BCBL-1 cells via caspase activation in a dose- and time-dependent manner. In addition, CuB caused cell-shape disruption by inducing actin aggregation and suppressing the p-cofilin level, resulting in BCBL-1 cell arrest at the G2/M phase. In contrast, CuB showed almost no suppression of p-STAT3 and p-Akt activation, which were constitutively activated by KSHV-derived proteins. Furthermore, CuB (0.5 mg/kg) via intraperitoneal injection significantly (p < 0.05) suppressed solid tumor growth in the xenograft mouse model.

Conclusion: This study suggests that CuB is a promising agent for PEL treatment.
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http://dx.doi.org/10.1016/j.phymed.2021.153545DOI Listing
March 2021

Ribosome induces transdifferentiation of A549 and H-111-TC cancer cell lines.

Biochem Biophys Rep 2021 Jul 12;26:100946. Epub 2021 Feb 12.

Department of Developmental Neurobiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, 860-8556, Japan.

Previously we reported that, lactic acid bacteria (LAB) can induce human dermal fibroblast (HDF) cells to form multipotent cell clusters which are able to transdifferentiate into three germ layer derived cell lineages. Later on, we confirmed that ribosome is responsible for the LAB-induced transdifferentiation and ribosomes from diverse organisms can mimic the LAB effect on HDF cells. In our present study we have shown that, upon incorporation of ribosomes, non-small cell lung cancer cell line A549 and gastric tubular adenocarcinoma cell line H-111-TC are transformed into spheroid like morphology those can be transdifferentiated into adipocytes and osteoblast. Our qPCR analysis has revealed that, during the formation of ribosome induced cancer cell spheroids, the expression of the cancer cell associated markers and cell cycle/proliferation markers were altered at different time point. Through our investigation, here we report a novel and a non-invasive approach for cancer cell reprogramming by incorporating ribosomes.
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http://dx.doi.org/10.1016/j.bbrep.2021.100946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887644PMC
July 2021

Modified Riceberry rice extract suppresses melanogenesis-associated cell differentiation through tyrosinase-mediated MITF downregulation on B16 cells and zebrafish embryos.

Res Pharm Sci 2020 Oct 19;15(5):491-502. Epub 2020 Oct 19.

Department of Pathobiology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand.

Background And Purpose: Excessive melanin production caused by overactive tyrosinase (TYR) enzyme results in several dermatological problems. The TYR inhibitor, derived from metabolite changes during fermentation, has been well recognized for pigmentation control.

Experimental Approach: This study is interested in alternative anti-melanogenic agents from bio-modified Riceberry rice through fermentation. Modified Riceberry rice extract (MRB) was evaluated for its cytotoxicity, melanin content, melanin excretion, and TYR activity in B16 cells. TYR and their melanogenesis-related molecules such as TYR-related proteins-1 and -2, and microphthalmia-associated transcription factor (MITF) were determined. The anti-melanogenic activity and toxicity were also tested using the embryonic zebrafish model. Furthermore, comprehensive genotoxicity testing was verified by cytokinesis-block micronucleus cytome assay.

Findings/results: The study found that non-cytotoxic concentrations of MRB at 20 and 40 mg/mL inhibited melanogenesis and melanin excretion by interfering B16 cell morphology. Cellular TYR enzymatic activity was also suppressed in the treated cells. The mRNA transcription and protein expression levels of TYR and MITF decreased by dose-dependent and time-dependent manners with MRB treatment. In the animal model, MRB was found to be safe and potent for melanogenesis-related TYR inhibition in embryonic zebrafish at 20 and 30 mg/mL. The toxicity of effective doses of MRB showed no genotoxicity and mutagenicity.

Conclusion And Implications: This study suggests that MRB has anti-melanogenesis potential through TYR and its-related protein inhibitions. MRB is also safe for applications and maybe a promising anti-melanogenic agent for hyperpigmentation control.
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http://dx.doi.org/10.4103/1735-5362.297852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879784PMC
October 2020

Inflammation-driven senescence-associated secretory phenotype in cancer-associated fibroblasts enhances peritoneal dissemination.

Cell Rep 2021 Feb;34(8):108779

Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; Gastrointestinal Cancer Biology, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan. Electronic address:

In the tumor microenvironment, senescent non-malignant cells, including cancer-associated fibroblasts (CAFs), exhibit a secretory profile under stress conditions; this senescence-associated secretory phenotype (SASP) leads to cancer progression and chemoresistance. However, the role of senescent CAFs in metastatic lesions and the molecular mechanism of inflammation-related SASP induction are not well understood. We show that pro-inflammatory cytokine-driven EZH2 downregulation maintains the SASP by demethylating H3K27me3 marks in CAFs and enhances peritoneal tumor formation of gastric cancer (GC) through JAK/STAT3 signaling in a mouse model. A JAK/STAT3 inhibitor blocks the increase in GC cell viability induced by senescent CAFs and peritoneal tumor formation. Single-cell mass cytometry revealed that fibroblasts exist in the ascites of GC patients with peritoneal dissemination, and the fibroblast population shows p16 expression and SASP factors at high levels. These findings provide insights into the inflammation-related SASP maintenance by histone modification and the role of senescent CAFs in GC peritoneal dissemination.
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http://dx.doi.org/10.1016/j.celrep.2021.108779DOI Listing
February 2021

Induction of apoptosis by Shikonin through ROS-mediated intrinsic and extrinsic apoptotic pathways in primary effusion lymphoma.

Transl Oncol 2021 Mar 2;14(3):101006. Epub 2021 Jan 2.

Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection, Kumamoto University, 2-2-1, Honjo, Kumamoto, 860-0811, Japan. Electronic address:

Primary effusion lymphoma (PEL) is an incurable non-Hodgkin's lymphoma and novel biology-based treatments are urgently needed in clinical settings. Shikonin (SHK), a napthoquinone derivative, has been used for the treatment of solid tumors. Here, we report that SHK is an effective agent for the treatment of PEL. Treatment with SHK results in significant reduction of proliferation in PEL cells and their rapid apoptosis in vitro. SHK-induced apoptosis of PEL cells is accompanied by the generation of reactive oxygen species (ROS), loss of mitochondrial membrane potential (Δψm), an activation of c-Jun-N-terminal kinase (JNK), p38, as well as caspase-3, -8, and -9. Scavenging of ROS in the presence of N-acetylcysteine (NAC) almost blocks the loss of mitochondrial membrane Δψm, activation of JNK, cleavage of caspase-3, -9, and an induction of apoptosis in SHK treated PEL cells. SP600125, a specific inhibitor of JNK, also rescues a proportion of cells from the apoptotic effect of SHK. In addition, inhibition of caspase activation in the presence of pan-caspase inhibitor, Q-VD-OPh, blocks the SHK-inducing apoptosis, but doesn't completely inhibit SHK-mediated JNK activation. Therefore, ROS is an upstream trigger of SHK-induced caspase dependent apoptosis of PEL cells through disruption of mitochondrial membrane Δψm in an intrinsic pathway and an activation of JNK in an extrinsic pathway. In a PEL xenografted mouse model, SHK treatment suppresses PEL-mediated ascites formation without showing any significant adverse toxicity. These results suggested that SHK could be a potent anti-tumor agent for the treatment of PEL.
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http://dx.doi.org/10.1016/j.tranon.2020.101006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785961PMC
March 2021

Anti-human CD99 antibody exerts potent antitumor effects in mantle cell lymphoma.

Cancer Immunol Immunother 2020 Nov 19. Epub 2020 Nov 19.

Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection and Graduate School of Medical Sciences, Kumamoto University, Kumamoto, 860-0811, Japan.

CD99 is a surface molecule expressed on various cell types including cancer cells. Expression of CD99 on multiple myeloma is associated with CCND1-IGH fusion/t(11;14). This translocation has been reported to be a genetic hallmark of mantle cell lymphoma (MCL). MCL is characterized by overexpression of cyclin D1 and high tumor proliferation. In this study, high expression of CD99 on MCL cell lines was confirmed. Our generated anti-CD99 monoclonal antibody (mAb), termed MT99/3, exerted potent antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) activities against mantle B-cell lymphoma without direct cytotoxic effects. The anti-tumor activities of mAb MT99/3 were more effective in MCL than in other B-cell lymphomas. Moreover, in a mouse xenograft model using Z138 MCL cell line, treatment of mAb MT99/3 reduced tumor development and growth. Our study indicated that mAb MT99/3 is a promising immunotherapeutic candidate for mantle cell lymphoma therapy.
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http://dx.doi.org/10.1007/s00262-020-02789-0DOI Listing
November 2020

Establishment of bone marrow-derived M-CSF receptor-dependent self-renewing macrophages.

Cell Death Discov 2020 23;6:63. Epub 2020 Jul 23.

Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, 860-0811 Japan.

Recent studies have revealed that tissue macrophages are derived from yolk sac precursors or fetal liver monocytes, in addition to bone marrow monocytes. The relative contribution of these cells to the tissue macrophage pool is not fully understood, but embryo-derived cells are supposed to be more important because of their capacity to self-renew. Here, we show the presence of adult bone marrow-derived macrophages that retain self-renewing capacity. The self-renewing macrophages were readily obtained by long-term culture of mouse bone marrow cells with macrophage colony-stimulating factor (M-CSF), a key cytokine for macrophage development. They were non-tumorigenic and proliferated in the presence of M-CSF in unlimited numbers. Despite several differences from non-proliferating macrophages, they retained many features of cells of the monocytic lineage, including the differentiation into dendritic cells or osteoclasts. Among the transcription factors involved in the self-renewal of embryonic stem cells, Krüppel-like factor 2 (KLF2) was strongly upregulated upon M-CSF stimulation in the self-renewing macrophages, which was accompanied by the downregulation of MafB, a transcription factor that suppresses KLF2 expression. Indeed, knockdown of KLF2 led to cell cycle arrest and diminished cell proliferation in the self-renewing macrophages. Our new cell model would be useful to unravel differences in phenotype, function, and molecular mechanism of proliferation among self-renewing macrophages with different origins.
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http://dx.doi.org/10.1038/s41420-020-00300-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378060PMC
July 2020

Chromomycin A3 suppresses cholangiocarcinoma growth by induction of S phase cell cycle arrest and suppression of Sp1‑related anti‑apoptotic proteins.

Int J Mol Med 2020 Apr 29;45(4):1005-1016. Epub 2020 Jan 29.

Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.

Cholangiocarcinoma (CCA) is a cancer of biliary epithelium. Late diagnosis and resistance to conventional chemotherapy are the major obstacles in CCA treatment. Increased expression of anti‑apoptotic proteins are observed in CCA, which might confer chemoresistance. Thus, modulations of anti‑apoptotic proteins leading to apoptotic induction is the focus of this study. Chromomycin A3 (CMA3), an anthraquinone glycoside‑mithramycin A analog, was selected. CMA3 strongly binds to GC‑rich regions in DNA, where specificity protein 1 (Sp1), a common transcription factor of apoptosis‑related proteins, is preferentially bounded. The effects of CMA3 on anti‑proliferation, cell cycle arrest and apoptosis induction in CCA cells were demonstrated by MTT assay, flow cytometry and western blot analysis. The results showed CMA3 suppressed cell proliferation in vitro in the nM range. At low doses, CMA3 inhibited cell cycle progression at S phase, while it promoted caspase‑dependent apoptosis at higher doses. CMA3 induced effects of apoptosis were through the suppression of Sp1‑related anti‑apoptotic proteins, FADD‑like IL‑1β‑converting enzyme‑inhibitory protein, myeloid cell leukemia‑1, X‑linked inhibitor of apoptosis protein, cellular inhibitor of apoptosis and survivin. The anti‑CCA effects of CMA3 were confirmed in the xenograft mouse model. CMA3 retarded xenograft tumor growth. Taken together, CMA3 induced apoptosis in CCA cells by diminishing the Sp1‑related anti‑apoptotic proteins is demonstrated. CMA3 might be useful as a chemosensitizing agent.
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http://dx.doi.org/10.3892/ijmm.2020.4482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053871PMC
April 2020

Terminal fucose mediates progression of human cholangiocarcinoma through EGF/EGFR activation and the Akt/Erk signaling pathway.

Sci Rep 2019 11 21;9(1):17266. Epub 2019 Nov 21.

Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand.

Aberrant glycosylation is recognized as a cancer hallmark that is associated with cancer development and progression. In this study, the clinical relevance and significance of terminal fucose (TFG), by fucosyltransferase-1 (FUT1) in carcinogenesis and progression of cholangiocarcinoma (CCA) were demonstrated. TFG expression in human and hamster CCA tissues were determined using Ulex europaeus agglutinin-I (UEA-I) histochemistry. Normal bile ducts rarely expressed TFG while 47% of CCA human tissues had high TFG expression and was correlated with shorter survival of patients. In the CCA-hamster model, TFG was elevated in hyperproliferative bile ducts and gradually increased until CCA was developed. This evidence indicates the involvement of TFG in carcinogenesis and progression of CCA. The mechanistic insight was performed in 2 CCA cell lines. Suppression of TFG expression using siFUT1 or neutralizing the surface TFG with UEA-I significantly reduced migration, invasion and adhesion of CCA cells in correlation with the reduction of Akt/Erk signaling and epithelial-mesenchymal transition. A short pulse of EGF could stimulate Akt/Erk signaling via activation of EGF-EGFR cascade, however, decreasing TFG using siFUT1 or UEA-I treatment reduced the EGF-EGFR activation and Akt/Erk signaling. This evidence provides important insight into the relevant role and molecular mechanism of TFG in progression of CCA.
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http://dx.doi.org/10.1038/s41598-019-53601-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872661PMC
November 2019

CD147 augmented monocarboxylate transporter-1/4 expression through modulation of the Akt-FoxO3-NF-κB pathway promotes cholangiocarcinoma migration and invasion.

Cell Oncol (Dordr) 2020 Apr 15;43(2):211-222. Epub 2019 Nov 15.

Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40005, Thailand.

Purpose: Cholangiocarcinoma (CCA) is an aggressive type of cancer. The major obstacles for treatment are its late presentation and the occurrence metastases. Targeting the metastatic process may serve as a treatment option. CD147 is a membrane protein that promotes CCA metastasis. High lactate levels in CCA are predicted to result from lactate dehydrogenase A expression and sensitivity to monocarboxylate transporter (MCT) inhibitors. An involvement of CD147 in MCT maturation has been reported, but the exact role of MCT in CCA is not clear. Here, we aimed to assess the mechanism of CD147-promoted CCA progression through MCT regulation.

Methods: The expression levels of CD147 and MCT-1/4 in human CCA tissues were determined by immunohistochemistry. Two CD147 knockout (CD147 KO) CCA cell (KKU-213) clones were established using the CRISPR/Cas9 system. Cell migration and invasion were determined using a Boyden chamber assay. Temporal protein levels were modified by siRNA, specific inhibitors and/or activators. The expression of target proteins was determined using Western blot analyses.

Results: CD147 and MCT-1/4 were found to be overexpressed in CCA tissues compared to normal bile duct tissues. In addition, we found that CD147 knockdown significantly alleviated CCA cell migration and invasion, concomitant with decreased pAkt, pFoxO3, pNF-κB (pp65) and MCT-1/4 levels. Conversely, we found that FoxO3 knockdown led to recovered migration/invasion abilities and increased pp65 and MCT-1/4 expression levels. The involvement of Akt in the regulation of MCT-1/4 expression through CD147 was established by inhibition and activation of Akt phosphorylation.

Conclusion: Our data indicate that CD147 promotes the malignant progression of CCA cells by activating the Akt-FoxO3-NF-κB-MCT-1/4 axis. As such, CD147 may serve as a possible target for advanced CCA treatment.
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http://dx.doi.org/10.1007/s13402-019-00479-3DOI Listing
April 2020

Ephedrine enhances HIV-1 reactivation from latency through elevating tumor necrosis factor receptor II (TNFRII) expression.

Heliyon 2019 Sep 26;5(9):e02490. Epub 2019 Sep 26.

Division of Hematopoiesis, Graduate School of Medical Sciences, and Joint Research Center for Human Retrovirus Infection, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto, 860-0811, Japan.

HIV-1 persists during antiretroviral therapy (ART) due to long-lived and proliferating latently-infected host cells, with the outcome being an incomplete cure. The latently-infected cells, or reservoir cells, are transcriptionally absent and invisible to the immune response. Elimination of latency is one strategy in activating virus production, making it visible to immune clearance. We previously showed that Ephedrae herba reactivated HIV-1 from latency. In this study, we used ephedrine, a major component of Ephedra herba, to reactivate HIV-1 from latency. The results showed that ephedrine enhances HIV-1 reactivation in the presence of TNFα. Combination treatment demonstrates a synergistic effect of HIV-1 reactivation compared to TNFα alone. Ephedrine treatment shows a higher TNFRII expression level, which is related to increased HIV-1 reactivation. However, the mechanism of ephedrine in HIV-1 reactivation is still unclear, and may be related to TNFRII receptor expression. Our results indicate that ephedrine enhances HIV-1 reactivation from latency in combination with TNFα treatment. This new reagent could be a promising latency reversal agent (LRA).
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http://dx.doi.org/10.1016/j.heliyon.2019.e02490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819846PMC
September 2019

Application of Highly Immunocompromised Mice for the Establishment of Patient-Derived Xenograft (PDX) Models.

Cells 2019 08 13;8(8). Epub 2019 Aug 13.

Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto 860-0811, Japan.

Patient-derived xenograft (PDX) models are created by engraftment of patient tumor tissues into immunocompetent mice. Since a PDX model retains the characteristics of the primary patient tumor including gene expression profiles and drug responses, it has become the most reliable in vivo human cancer model. The engraftment rate increases with the introduction of Non-obese diabetic Severe combined immunodeficiency (NOD/SCID)-based immunocompromised mice, especially the NK-deficient NOD strains NOD/SCID/interleukin-2 receptor gamma chain(IL2Rγ)NOG/NSG) and NOD/SCID/Jak3(Janus kinase 3) (NOJ). Success rates differ with tumor origin: gastrointestinal tumors acquire a higher engraftment rate, while the rate is lower for breast cancers. Subcutaneous transplantation is the most popular method to establish PDX, but some tumors require specific environments, e.g., orthotropic or renal capsule transplantation. Human hormone treatment is necessary to establish hormone-dependent cancers such as prostate and breast cancers. PDX mice with human hematopoietic and immune systems (humanized PDX) are powerful tools for the analysis of tumor-immune system interaction and evaluation of immunotherapy response. A PDX biobank equipped with patients' clinical data, gene-expression patterns, mutational statuses, tumor tissue architects, and drug responsiveness will be an authoritative resource for developing specific tumor biomarkers for chemotherapeutic predictions, creating individualized therapy, and establishing precise cancer medicine.
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http://dx.doi.org/10.3390/cells8080889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721637PMC
August 2019

Antitumor effects of flavopiridol, a cyclin-dependent kinase inhibitor, on human cholangiocarcinoma and in an xenograft model.

Heliyon 2019 May 9;5(5):e01675. Epub 2019 May 9.

Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, Kumamoto 860-0811, Japan.

Flavopiridol, a pan-cyclin-dependent kinase (CDK) inhibitor, was recently identified as an effective antitumor agent for several cancers. We investigated the antitumor effect of flavopiridol on cholangiocarcinoma (CCA), and . A methylthiotetrazole assay revealed that the proliferation of certain CCA cells was inhibited by flavopiridol, which induced the caspase-dependent apoptosis of CCA cells. Although increased cell cycle arrest was observed at the G2/M phase, caspase activation occurred earlier than 24 h, indicating that caspase-dependent apoptosis is the major pathway for the suppression of cell proliferation. Flavopiridol potently reduced the CCA tumor growth in a xenograft model without observable adverse effects. These findings indicated that flavopiridol could be a potential antitumor agent for the treatment of CCA.
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http://dx.doi.org/10.1016/j.heliyon.2019.e01675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6515137PMC
May 2019

Establishment of Highly Transplantable Cholangiocarcinoma Cell Lines from a Patient-Derived Xenograft Mouse Model.

Cells 2019 05 23;8(5). Epub 2019 May 23.

Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection and Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-0811, Japan.

Cholangiocarcinoma (CCA) is a deadly malignant tumor of the liver. It is a significant health problem in Thailand. The critical obstacles of CCA diagnosis and treatment are the high heterogeneity of disease and considerable resistance to treatment. Recent multi-omics studies revealed the promising targets for CCA treatment; however, limited models for drug discovery are available. This study aimed to develop a patient-derived xenograft (PDX) model as well as PDX-derived cell lines of CCA for future drug screening. From a total of 16 CCA frozen tissues, 75% (eight intrahepatic and four extrahepatic subtypes) were successfully grown and subpassaged in Balb/c Rag-2/Jak3 mice. A shorter duration of PDX growth was observed during F0 to F2 transplantation; concomitantly, increased Oct-3/4 and Sox2 were evidenced in 50% and 33%, respectively, of serial PDXs. Only four cell lines were established. The cell lines exhibited either bile duct (KKK-D049 and KKK-D068) or combined hepatobiliary origin (KKK-D131 and KKK-D138). These cell lines acquired high transplantation efficiency in both subcutaneous (100%) and intrasplenic (88%) transplantation models. The subcutaneously transplanted xenograft retained the histological architecture as in the patient tissues. Our models of CCA PDX and PDX-derived cell lines would be a useful platform for CCA precision medicine.
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http://dx.doi.org/10.3390/cells8050496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562875PMC
May 2019

Attenuation of CD47-SIRPα Signal in Cholangiocarcinoma Potentiates Tumor-Associated Macrophage-Mediated Phagocytosis and Suppresses Intrahepatic Metastasis.

Transl Oncol 2019 Feb 9;12(2):217-225. Epub 2018 Nov 9.

Division of Hematopoiesis, Center for AIDS research and Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. Electronic address:

The involvement of chronic inflammation in cholangiocarcinoma (CCA) progression is well established. Cluster of differentiation 47 (CD47) is mutually expressed in various cancers and serves as a protective signal for phagocytic elimination. CD47 signaling blockage is a recent treatment strategy; however, little is known regarding CD47 in CCA. Therefore, the potential use of CD47 targeting in CCA was focused. CD47 was highly expressed in CCA compared to hepatocellular carcinoma (HCC). Disturbance of CD47-signal regulatory protein-α (SIRPα) interaction by blocking antibodies promoted the macrophage phagocytosis. The therapeutic potential of anti-CD47 therapy was demonstrated in liver metastatic model; alleviation of cancer colonization together with dense macrophage infiltrations was observed. The usefulness of anti-CD47 was emphasized by its universal facilitating macrophage activities. Moreover, increased production of inflammatory cytokines, such as IL-6 and IL-10, in macrophage exposed to CCA-conditioned media suggested that CCA alters macrophages toward cancer promotion. Taken together, interfering of CD47-SIRPα interaction promotes macrophage phagocytosis in all macrophage subtypes and consequently suppresses CCA growth and metastasis. The unique overexpression of CD47 in CCA but not HCC offers an exceptional opportunity for a targeted therapy. CD47 is therefore a novel target for CCA treatment.
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http://dx.doi.org/10.1016/j.tranon.2018.10.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6231245PMC
February 2019

HIV-1 Vpr and p21 restrict LINE-1 mobility.

Nucleic Acids Res 2018 09;46(16):8454-8470

Center for AIDS Research, Kumamoto University, Kumamoto 860-0811, Japan.

Long interspersed element-1 (LINE-1, L1) composes ∼17% of the human genome. However, genetic interactions between L1 and human immunodeficiency virus type 1 (HIV-1) remain poorly understood. In this study, we found that HIV-1 suppresses L1 retrotransposition. Notably, HIV-1 Vpr strongly inhibited retrotransposition without inhibiting L1 promoter activity. Since Vpr is known to regulate host cell cycle, we examined the possibility whether Vpr suppresses L1 retrotransposition in a cell cycle dependent manner. We showed that the inhibitory effect of a mutant Vpr (H71R), which is unable to arrest the cell cycle, was significantly relieved compared with that of wild-type Vpr, suggesting that Vpr suppresses L1 mobility in a cell cycle dependent manner. Furthermore, a host cell cycle regulator p21Waf1 strongly suppressed L1 retrotransposition. The N-terminal kinase inhibitory domain (KID) of p21 was required for this inhibitory effect. Another KID-containing host cell cycle regulator p27Kip1 also strongly suppressed L1 retrotransposition. We showed that Vpr and p21 coimmunoprecipitated with L1 ORF2p and they suppressed the L1 reverse transcriptase activity in LEAP assay, suggesting that Vpr and p21 inhibit ORF2p-mediated reverse transcription. Altogether, our results suggest that viral and host cell cycle regulatory machinery limit L1 mobility in cultured cells.
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http://dx.doi.org/10.1093/nar/gky688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6144823PMC
September 2018

Establishment of a Patient-Derived Tumor Xenograft Model and Application for Precision Cancer Medicine.

Chem Pharm Bull (Tokyo) 2018 ;66(3):225-230

Center for AIDS Resesarch, Kumamoto University.

Patient-derived xenograft (PDX) models can be created with the transplantation of cancerous cells or tissues from patients' primary tumors into immunodeficient mice. PDXs are now in the spotlight as more accurate human cancer models compared with mouse tumor and human cancer cell lines transplanted into mice. PDX technology leads to breakthroughs with the introduction of novel, highly immunodeficient mice such as NOG (NOD/Scid/IL2Rγ), NSG (NOD/Scid/IL2Rγ), and NOJ (NOD/Scid/Jak3) mice. Xenograft efficiency differs by type of tumor, site of implantation, and tumor aggressiveness. Subcutaneous implantation is a standard method for PDX, and renal capsule or orthotropic implantation improves the efficiency. Despite positive test results in animal cancer models, significant numbers of novel drug candidates fail in clinical trials because conventional animal models such as murine tumor and human cancer cell line transplantation models do not always reflect the nature of human cancers. Since PDXs conserve the original tumor characteristics such as heterogeneous histology, clinical biomolecular signatures, malignant phenotypes and genotypes, tumor architecture, and tumor vasculature, they are currently believed to offer relevant predictive insights into clinical outcomes when evaluating the efficacy of novel cancer therapies. PDX banks with integrated genomic signatures are now established in many organizations including pharmaceutical companies. These PDX databases are becoming powerful tools for advancing precision cancer medicine.
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http://dx.doi.org/10.1248/cpb.c17-00789DOI Listing
March 2018

Repurposing cimetidine for cholangiocarcinoma: Antitumor effects and .

Oncol Lett 2017 Mar 2;13(3):1432-1436. Epub 2017 Jan 2.

Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, Kumamoto 860-0811, Japan.

Cimetidine is a histamine type-2 (H) receptor antagonist that has been demonstrated to have antitumor effects on various types of malignancy. However, its effect on cholangiocarcinoma (CCA), a chemotherapy-resistant bile duct tumor, has yet to be investigated. In the present study, the antitumor activity of cimetidine and was evaluated. A methylthiotetrazole assay revealed that the proliferation of certain CCA cell lines was inhibited by cimetidine, which induced the caspase-dependent apoptosis of CCA cells via suppression of the protein kinase B signaling pathway. Suppression of Akt phosphorylation, caspase-3, -8 and -9 activation, phosphotidylserine exposure determined by Annexin V binding assay and the presence of a sub-G1 population were demonstrated by western blotting and flow cytometry analysis. In a CCA xenograft mouse model cimetidine inhibited the growth of CCA cells without observable adverse effects. These results suggest that cimetidine has the potential to be an effective antitumor agent for the treatment of CCA.
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http://dx.doi.org/10.3892/ol.2017.5563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5403332PMC
March 2017

Upregulation of CD147 Promotes Metastasis of Cholangiocarcinoma by Modulating the Epithelial-to-Mesenchymal Transitional Process.

Oncol Res 2017 Aug 15;25(7):1047-1059. Epub 2016 Dec 15.

CD147 is a transmembrane protein that can induce the expression and activity of matrix metalloproteinases (MMPs). Expression of CD147 has been shown to potentiate cell migration, invasion, and metastasis of cancer. In this study, the critical role of CD147 in metastasis was elucidated using CD147-overexpressing cholangiocarcinoma (CCA) cells in vitro and in vivo. The molecular mechanism, demonstrated herein, supported the hypothesis that metastasis increased in CD147-overexpressing cells. Five CD147-overexpressing clones (Ex-CD147) were established from a low CD147-expressing CCA cell line, KKU-055, using lentivirus containing pReceiver-Lenti-CD147. The metastatic capability was determined using the tail vein injection mouse model and an in vitro 3D invasion assay. Liver colonization was assessed using anti-HLA class I immunohistochemistry. Adhesion abilities, cytoskeletal arrangements, MMP activities, the expressions of adhesion molecules, and epithelial-mesenchymal transitional markers were analyzed. All Ex-CD147 clones exhibited a high CD147 expression and high liver colonization in the tail vein-injected mouse model, whereas parental cells lacked this ability. Ex-CD147 clones exhibited metastatic phenotypes (i.e., an increase in F-actin rearrangement) and cell invasion and a decrease in cell adhesion. The molecular mechanisms were shown to be via the induction of MMP-2 activity and enhancement of epithelial-mesenchymal transitions. An increase in mesenchymal markers Slug, vimentin, and N-cadherin, and a decrease in epithelial markers E-cadherin and claudin-1, together with suppression of the adhesion molecule ICAM-1, were observed in the Ex-CD147 clones. Moreover, suppression of CD147 expression using siCD147 in two CCA cell lines with high CD147 expression significantly decreased cell migration and invasion of these CCA cells. These findings emphasize the essential role of CD147 in CCA metastasis and suggest CD147 as a promising target for the effective treatment of CCA.
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http://dx.doi.org/10.3727/096504016X14813899000565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841082PMC
August 2017

The MEK inhibitor trametinib separates murine graft-versus-host disease from graft-versus-tumor effects.

JCI Insight 2016 07 7;1(10):e86331. Epub 2016 Jul 7.

Department of Hematology, Respiratory Medicine and Oncology, Saga University School of Medicine, Saga, Japan.

The efficacy of allogeneic hematopoietic stem cell transplantation for hematologic malignancies is limited by the difficulty in suppressing graft-versus-host disease (GVHD) without compromising graft-versus-tumor (GVT) effects. We previously showed that RAS/MEK/ERK signaling depends on memory differentiation in human T cells, which confers susceptibility to selective inhibition of naive T cells. Actually, antineoplastic MEK inhibitors selectively suppress alloreactive T cells, sparing virus-specific T cells in vitro. Here, we show that trametinib, a MEK inhibitor clinically approved for melanoma, suppresses GVHD safely without affecting GVT effects in vivo. Trametinib prolonged survival of GVHD mice and attenuated GVHD symptoms and pathology in the gut and skin. It inhibited ERK1/2 phosphorylation and expansion of donor T cells, sparing Tregs and B cells. Although high-dose trametinib inhibited myeloid cell engraftment, low-dose trametinib suppressed GVHD without severe adverse events. Notably, trametinib facilitated the survival of mice transplanted with allogeneic T cells and P815 tumor cells with no residual P815 cells observed in the livers and spleens, whereas tacrolimus resulted in P815 expansion. These results confirm that trametinib selectively suppresses GVHD-inducing T cells while sparing antitumor T cells in vivo, which makes it a promising candidate for translational studies aimed at preventing or treating GVHD.
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http://dx.doi.org/10.1172/jci.insight.86331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5033881PMC
July 2016

Inhibition of autophagy by chloroquine induces apoptosis in primary effusion lymphoma in vitro and in vivo through induction of endoplasmic reticulum stress.

Apoptosis 2016 10;21(10):1191-201

Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, 2-2-1, Honjo, Kumamoto, 860-0811, Japan.

Autophagy plays a crucial role in cancer cell survival and the inhibition of autophagy is attracting attention as an emerging strategy for the treatment of cancer. Chloroquine (CQ) is an anti-malarial drug, and is also known as an inhibitor of autophagy. Recently, it has been found that CQ induces cancer cell death through the inhibition of autophagy; however, the underlying mechanism is not entirely understood. In this study, we identified the role of CQ-induced cancer cell death using Primary Effusion Lymphoma (PEL) cells. We found that a CQ treatment induced caspase-dependent apoptosis in vitro. CQ also suppressed PEL cell growth in a PEL xenograft mouse model. We showed that CQ activated endoplasmic reticulum (ER) stress signal pathways and induced CHOP, which is an inducer of apoptosis. CQ-induced cell death was significantly decreased by salbrinal, an ER stress inhibitor, indicating that CQ-induced apoptosis in PEL cells depended on ER stress. We show here for the first time that the inhibition of autophagy induces ER stress-mediated apoptosis in PEL cells. Thus, the inhibition of autophagy is a novel strategy for cancer chemotherapy.
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http://dx.doi.org/10.1007/s10495-016-1277-7DOI Listing
October 2016

A potential role of the NOD genetic background in mouse peritoneal macrophages for the development of primary effusion lymphoma.

Leuk Res 2016 Mar 28;42:37-42. Epub 2016 Jan 28.

Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, Honjo, Kumamoto, Japan. Electronic address:

Severe immunodeficient mice have become invaluable tools in human stem cell and tumor research. In this study, we compared the phagocytic activity of peritoneal macrophages against primary effusion lymphoma (PEL) among Rag-2/Jak3 double-deficient (Rag-2(-/-)Jak3(-/-)) mice with NOD and non-NOD (Balb/c and C57/BL6). We also evaluated lymphomatous effusion and infiltration in a PEL xenograft mouse model using these severe immunodeficient mice. In the phagocytic assay, peritoneal macrophages in the NOD background phagocytosed CFSE-labeled BCBL-1, a PEL cell line, less efficiently than those in the non-NOD background. BCBL-1 cells were successfully engrafted into both the NOD background and non-NOD background; however, the volume of ascites of the NOD background was significantly higher than that of the non-NOD background. Moreover, the organ invasion of PEL cells was suppressed in non-NOD background mice. Thus, the NOD genetic background is considered to contribute to more lymphomatous effusion and the infiltration of PEL cells than a non-NOD background. Our results showed that the NOD background allowed more lymphomatous effusion and infiltration than other backgrounds and peritoneal macrophages played a critical role in preventing the growth and infiltration of PEL cells.
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http://dx.doi.org/10.1016/j.leukres.2016.01.011DOI Listing
March 2016

Inhibition of carbonic anhydrase potentiates bevacizumab treatment in cholangiocarcinoma.

Tumour Biol 2016 Jul 13;37(7):9023-35. Epub 2016 Jan 13.

Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, 2-2-1 Honjo, Kumamoto, 860-0811, Japan.

Cholangiocarcinoma (CCA) is a unique liver cancer subtype with an increasing incidence globally. The lack of specific symptoms and definite diagnostic markers results in a delayed diagnosis and disease progression. Systemic chemotherapy is commonly selected for advanced CCA even though its advantages remain unknown. Targeted therapy, especially anti-vascular endothelial growth factor (VEGF) therapy, is promising for CCA; however, improvements in the therapeutic regimen are necessary to overcome subsequent resistance. We demonstrated VEGF expression was higher in CCA cell lines than in other liver cancer cells. Secreted VEGFs played roles in the induction of peri- and intra-tumoral vascularization. VEGF neutralization by bevacizumab effectively reduced tumor growth, mainly through the suppression of angiogenesis; however, increases in the expression of hypoxia-inducible factor 1α (HIF1α) and HIF1α-responsive genes (such as VEGF, VEGFR1, VEGFR2, carbonic anhydrase (CA) IX and CAXII) indicated the potential for subsequent therapeutic resistance. Supplementation with a carbonic anhydrase inhibitor, acetazolamide, enhanced the anti-CCA effects of bevacizumab. Anti-angiogenesis and anti-proliferation were observed with the combination treatment. These results suggested a novel treatment strategy to overcome anti-angiogenesis resistance and the importance of "induced essentiality" in the treatment of CCA.
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http://dx.doi.org/10.1007/s13277-016-4785-8DOI Listing
July 2016

Proliferation of functional human natural killer cells with anti-HIV-1 activity in NOD/SCID/Jak3(null) mice.

Microbiol Immunol 2016 Feb;60(2):106-13

Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, Kumamoto, Japan.

Natural killer cells, a critical component of the innate immune system, eradicate both virus-infected cells and tumor cells through cytotoxicity and secretion of cytokines. Human NK cell research has largely been based on in vitro studies because of the lack of appropriate animal models. In this study, a selective proliferation model of functional human NK cells was established in NOD/SCID/Jak3(null) (NOJ) mice transplanted with peripheral blood mononuclear cells (PBMC) and K562 cells. The antiviral effects of NK cells were evaluated by challenging this mouse model with HIV-1. The percentage of intracellular p24(+) T cells and the amount of plasma p24 was decreased compared with NOJ mice transplanted with PBMC. Our findings indicate that NK cells have an anti-HIV-1 effect through direct cytotoxicity against HIV-1-infected cells. These mice provide an important model for evaluating human NK function against human infectious diseases such as HIV-1 and malignancies.
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http://dx.doi.org/10.1111/1348-0421.12355DOI Listing
February 2016

Anti-inflammatory effects of activated protein C on human dendritic cells.

Microbiol Immunol 2015 Jul;59(7):381-8

Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, Kumamoto, Japan.

Activated protein C (APC) has an anticoagulant action and plays an important role in blood coagulation homeostasis. In addition to its anticoagulant action, APC is known to have cytoprotective effects, such as anti-apoptotic action and endothelial barrier protection, on vascular endothelial cells and monocytes. However, the effects of APC on DCs have not been clarified. To investigate the effects of APC on human DCs, monocytes were isolated from peripheral blood and DC differentiation induced with LPS. APC significantly inhibited the production of inflammatory cytokines TNF-α and IL-6 during differentiation of immature DCs to mature DCs, but did not inhibit the production of IL-12 and anti-inflammatory cytokine IL-10. Interestingly, treatment with 5 μg/mL, but not 25 μg/mL, of APC significantly enhanced production of IL-10. In addition, protein C, which is the zymogen of APC, did not affect production of these cytokines. On the other hand, flow cytometric analysis of DC's surface molecules indicated that APC does not significantly affect expression of CD83, a marker of mDC differentiation, and the co-stimulatory molecules CD40, CD80 and CD86. These results suggest that APC has anti-inflammatory effects on human DCs and may be effective against some inflammatory diseases in which the pathogenesis involves TNF-α and/or IL-6 production.
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http://dx.doi.org/10.1111/1348-0421.12262DOI Listing
July 2015

Evaluation of antitumor effects of folate-conjugated methyl-β-cyclodextrin in melanoma.

Biol Pharm Bull 2015 ;38(3):374-9

Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University.

Melanoma is a life-threatening disorder and its incidence is increasing gradually. Despite the numerous treatment approaches, conventional systemic chemotherapy has not reduced the mortality rate among melanoma patients, probably due to the induction of toxicity to normal tissues. Recently, we have developed folate-conjugated methyl-β-cyclodextrin (FA-M-β-CyD) and clarified its potential as a new antitumor agent involved in autophagic cell death. However, it remains uncertain whether FA-M-β-CyD exerts anticancer effects against melanomas. Therefore, in this study, we investigated the effects of FA-M-β-CyD on the folate receptor-α (FR-α)-expressing melanoma cell-selective cytotoxic effect. FA-M-β-CyD showed cytotoxic effects in Ihara cells, a human melanoma cell line expressing FR-α. In sharp contrast to methyl-β-cyclodextrin, FA-M-β-CyD entered Ihara cells [FR-α(+)] through FR-α-mediated endocytosis. Additionally, FA-M-β-CyD elicited the formation of autophagosomes in Ihara cells. Notably, FA-M-β-CyD suppressed melanoma growth in BALB/c nude recombinase-activating gene-2 (Rag-2)/Janus kinase 3 (Jak3) double deficient mice bearing Ihara cells. Therefore, these results suggest that FA-M-β-CyD could be utilized as a potent anticancer agent for melanoma chemotherapy by regulating autophagy.
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http://dx.doi.org/10.1248/bpb.b14-00531DOI Listing
November 2015

Inhibition of HIV-1 entry by the tricyclic coumarin GUT-70 through the modification of membrane fluidity.

Biochem Biophys Res Commun 2015 Feb 7;457(3):288-94. Epub 2015 Jan 7.

Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan. Electronic address:

Membrane fusion between host cells and HIV-1 is the initial step in HIV-1 infection, and plasma membrane fluidity strongly influences infectivity. In the present study, we demonstrated that GUT-70, a natural product derived from Calophyllum brasiliense, stabilized plasma membrane fluidity, inhibited HIV-1 entry, and down-regulated the expression of CD4, CCR5, and CXCR4. Since GUT-70 also had an inhibitory effect on viral replication through the inhibition of NF-κB, it is expected to be used as a dual functional and viral mutation resistant reagent. Thus, these unique properties of GUT-70 enable the development of novel therapeutic agents against HIV-1 infection.
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http://dx.doi.org/10.1016/j.bbrc.2014.12.102DOI Listing
February 2015

COMMD1/Murr1 reinforces HIV-1 latent infection through IκB-α stabilization.

J Virol 2015 Mar 17;89(5):2643-58. Epub 2014 Dec 17.

Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, Kumamoto, Japan

Unlabelled: The transcription factor NF-κB is important for HIV-1 transcription initiation in primary HIV-1 infection and reactivation in latently HIV-1-infected cells. However, comparative analysis of the regulation and function of NF-κB in latently HIV-1-infected cells has not been done. Here we show that the expression of IκB-α, an endogenous inhibitor of NF-κB, is enhanced by latent HIV-1 infection via induction of the host-derived factor COMMD1/Murr1 in myeloid cells but not in lymphoid cells by using four sets of latently HIV-1-infected cells and the respective parental cells. IκB-α protein was stabilized by COMMD1, which attenuated NF-κB signaling during Toll-like receptor ligand and tumor necrosis factor alpha treatment and enhanced HIV-1 latency in latently HIV-1-infected cells. Activation of the phosphoinositol 3-kinase (PI3K)-JAK pathway is involved in COMMD1 induction in latently HIV-1-infected cells. Our findings indicate that COMMD1 induction is the NF-κB inhibition mechanism in latently HIV-1-infected cells that contributes to innate immune deficiency and reinforces HIV-1 latency. Thus, COMMD1 might be a double-edged sword that is beneficial in primary infection but not beneficial in latent infection when HIV-1 eradication is considered.

Importance: HIV-1 latency is a major barrier to viral eradication in the era of combination antiretroviral therapy. In this study, we found that COMMD1/Murr1, previously identified as an HIV-1 restriction factor, inhibits the proteasomal degradation of IκB-α by increasing the interaction with IκB-α in latently HIV-1-infected myeloid cells. IκB-α protein was stabilized by COMMD1, which attenuated NF-κB signaling during the innate immune response and enhanced HIV-1 latency in latently HIV-1-infected cells. Activation of the PI3K-JAK pathway is involved in COMMD1 induction in latently HIV-1-infected cells. Thus, the host-derived factor COMMD1 is beneficial in suppressing primary infection but enhances latent infection, indicating that it may be a double-edged sword in HIV-1 eradication.
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http://dx.doi.org/10.1128/JVI.03105-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4325709PMC
March 2015

The antitumor effects of methyl-β-cyclodextrin against primary effusion lymphoma via the depletion of cholesterol from lipid rafts.

Biochem Biophys Res Commun 2014 Dec 11;455(3-4):285-9. Epub 2014 Nov 11.

Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, Kumamoto, Japan. Electronic address:

Primary effusion lymphoma (PEL) is a subtype of aggressive and chemotherapy-resistant non-Hodgkin lymphoma that occurs predominantly in patients with advanced AIDS. In this study, we examined the antitumor activity of methyl-β-cyclodextrin (M-β-CyD) in vitro and in vivo. M-β-CyD quickly induced caspase-dependent apoptosis in PEL cells via cholesterol depletion from the plasma membrane. In a PEL xenograft mouse model, M-β-CyD significantly inhibited the growth and invasion of PEL cells without apparent adverse effects. These results strongly suggest that M-β-CyD has the potential to be an effective antitumor agent against PEL.
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http://dx.doi.org/10.1016/j.bbrc.2014.11.006DOI Listing
December 2014