Publications by authors named "Leland W K Chung"

175 Publications

KDM6B is an androgen regulated gene and plays oncogenic roles by demethylating H3K27me3 at cyclin D1 promoter in prostate cancer.

Cell Death Dis 2021 Jan 6;12(1). Epub 2021 Jan 6.

Department of Urology, Changhai Hospital, Navy Medical University, 168 Changhai Road, Shanghai, 200433, China.

Lysine (K)-specific demethylase 6B (KDM6B), a stress-inducible H3K27me3 demethylase, plays oncogenic or antitumoral roles in malignant tumors depending on the type of tumor cell. However, how this histone modifier affects the progression of prostate cancer (PCa) is still unknown. Here we analyzed sequenced gene expression data and tissue microarray to explore the expression features and prognostic value of KDM6B in PCa. Further, we performed in vitro cell biological experiments and in vivo nude mouse models to reveal the biological function, upstream and downstream regulation mechanism of KDM6B. In addition, we investigated the effects of a KDM6B inhibitor, GSK-J4, on PCa cells. We showed that KDM6B overexpression was observed in PCa, and elevated KDM6B expression was associated with high Gleason Score, low serum prostate-specific antigen level and shorted recurrence-free survival. Moreover, KDM6B prompted proliferation, migration, invasion and cell cycle progression and suppressed apoptosis in PCa cells. GSK-J4 administration could significantly suppress the biological function of KDM6B in PCa cells. KDM6B is involved in the development of castration-resistant prostate cancer (CRPC), and combination of MDV3100 plus GSK-J4 is effective for CRPC and MDV3100-resistant CRPC. Mechanism exploration revealed that androgen receptor can decrease the transcription of KDM6B and that KDM6B demethylates H3K27me3 at the cyclin D1 promoter and cooperates with smad2/3 to prompt the expression of cyclin D1. In conclusion, our study demonstrates that KDM6B is an androgen receptor regulated gene and plays oncogenic roles by promoting cyclin D1 transcription in PCa and GSK-J4 has the potential to be a promising agent for the treatment of PCa.
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http://dx.doi.org/10.1038/s41419-020-03354-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791132PMC
January 2021

Intraoperative assessment and postsurgical treatment of prostate cancer tumors using tumor-targeted nanoprobes.

Nanotheranostics 2021 1;5(1):57-72. Epub 2021 Jan 1.

Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

Successful visualization of prostate cancer (PCa) tumor margins during surgery remains a major challenge. The visualization of these tumors during surgery via near infrared fluorescence (NIRF) imaging would greatly enhance surgical resection, minimizing tumor recurrence and improving outcome. Furthermore, chemotherapy is typically administered to patients after surgery to treat any missed tumor tissue around the surgical area, minimizing metastasis and increasing patient survival. For these reasons, a theranostics fluorescent nanoparticle could be developed to assist in the visualization of PCa tumor margins, while also delivering chemotherapeutic drug after surgery. Ferumoxytol (FMX) conjugated to the fluorescent dye and PCa targeting agent, heptamethine carbocyanine (HMC), yielded the HMC-FMX nanoprobe that was tested with various PCa cell lines and with both subcutaneous and orthotopic PCa mouse models. Visualization of these tumors NIRF imaging after administration of HMC-FMX was performed. In addition, delivery of chemotherapeutic drug and their effect on tumor growth was also assessed. HMC-FMX internalized into PCa cells, labeling these cells and PCa tumors in mice with near infrared fluorescence, facilitating tumor margin visualization. HMC-FMX was also able to deliver drugs to these tumors, reducing cell migration and slowing down tumor growth. HMC-FMX specifically targeted PCa tumors in mice allowing for the visualization of tumor margins by NIRF imaging. Furthermore, delivery of anticancer drugs by HMC-FMX effectively reduced prostate tumor growth and reduced cell migration . Thus, HMC-FMX can potentially translate into the clinic as a nanotheranostics agent for the intraoperative visualization of PCa tumor margins, and post-operative treatment of tumors with HMC-FMX loaded with anticancer drugs.
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http://dx.doi.org/10.7150/ntno.50095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738944PMC
January 2021

Near Infrared Fluorescent Nanoplatform for Targeted Intraoperative Resection and Chemotherapeutic Treatment of Glioblastoma.

ACS Nano 2020 07 23;14(7):8392-8408. Epub 2020 Jun 23.

Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, California 90048, United States.

Despite significant efforts to improve glioblastoma multiforme (GBM) treatment, GBM remains one of the most lethal cancers. Effective GBM treatments require sensitive intraoperative tumor visualization and effective postoperative chemotherapeutic delivery. Unfortunately, the diffusive and infiltrating nature of GBM limits the detection of GBM tumors, and current intraoperative visualization methods limit complete tumor resection. In addition, although chemotherapy is often used to eliminate any cancerous tissue remaining after surgery, most chemotherapeutic drugs do not effectively cross the brain-blood barrier (BBB) or enter GBM tumors. As a result, GBM has limited treatment options with high recurrence rates, and methods that improve its complete visualization during surgery and treatment are needed. Herein, we report a fluorescent nanoparticle platform for the near-infrared fluorescence (NIRF)-based tumor boundary visualization and image-guided drug delivery into GBM tumors. Our nanoplatform is based on ferumoxytol (FMX), an FDA-approved magnetic resonance imaging-sensitive superparamagnetic iron oxide nanoparticle, which is conjugated with hepthamethine cyanine (HMC), a NIRF ligand that specifically targets the organic anion transporter polypeptides that are overexpressed in GBM. We have shown that HMC-FMX nanoparticles cross the BBB and selectively accumulate in the tumor using orthotopic GBM mouse models, enabling NIRF-based visualization of infiltrating tumor tissue. In addition, HMC-FMX can encapsulate chemotherapeutic drugs, such as paclitaxel or cisplatin, and deliver these agents into GBM tumors, reducing tumor size and increasing survival. Taken together, these observations indicate that HMC-FMX is a promising nanoprobe for GBM surgical visualization and drug delivery.
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http://dx.doi.org/10.1021/acsnano.0c02509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7438253PMC
July 2020

Cancer cell's neuroendocrine feature can be acquired through cell-cell fusion during cancer-neural stem cell interaction.

Sci Rep 2020 01 27;10(1):1216. Epub 2020 Jan 27.

Uro-Oncology Research, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Advanced and therapy-resistant prostate tumors often display neural or neuroendocrine behavior. We assessed the consequences of prostate cancer cell interaction with neural cells, which are rich in the human prostate and resident of the prostate tumor. In 3-dimensional co-culture with neurospheres, red fluorescent human LNCaP cells formed agglomerates on the neurosphere surface. Upon induced neural differentiation, some red fluorescent cells showed morphology of fully differentiated neural cells, indicating fusion between the cancer and neural stem cells. These fusion hybrids survived for extended times in a quiescent state. A few eventually restarted cell division and propagated to form derivative hybrid progenies. Clones of the hybrid progenies were highly heterogeneous; most had lost prostatic and epithelial markers while some had acquired neural marker expression. These results indicate that cancer cells can fuse with bystander neural cells in the tumor microenvironment; and cancer cell fusion is a direct route to tumor cell heterogeneity.
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http://dx.doi.org/10.1038/s41598-020-58118-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6985266PMC
January 2020

Cancer-stromal cell fusion as revealed by fluorescence protein tracking.

Prostate 2020 02 17;80(3):274-283. Epub 2019 Dec 17.

Uro-Oncology Research, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.

Purpose: We previously determined that cancer-stromal interaction was a direct route to tumor cell heterogeneity progression, since cancer-stromal cell fusion in coculture resulted in the creation of heterogeneous clones of fusion hybrid progeny. In this report, we modified the cancer-stromal coculture system to establish optimal experimental conditions for investigating cell fusion machinery and the mechanism of heterogeneity progression.

Experimental Design: Red fluorescence protein-tagged LNCaP cells were cocultured with green fluorescence protein-labeled prostate stromal cells for cancer-stromal cell fusion, which was tracked as dual fluorescent cells by fluorescence microscopy.

Results: We identified the most efficient strategy to isolate clones of fusion hybrid progenies. From the coculture, mixed cells including fusion hybrids were subjected to low-density replating for colony formation by fusion hybrid progeny. These colonies could propagate into derivative cell populations. Compared to the parental LNCaP cells, clones of the fusion hybrid progeny displayed divergent behaviors and exhibited permanent genomic hybridization.

Conclusions: Cancer-stromal cell fusion leads to cancer cell heterogeneity. The cancer-stromal coculture system characterized in this study can be used as a model for molecular characterization of cancer cell fusion as the mechanism behind the progression of heterogeneity observed in clinical prostate cancers.
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http://dx.doi.org/10.1002/pros.23941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949378PMC
February 2020

A Novel Salicylanilide Derivative Induces Autophagy Cell Death in Castration-Resistant Prostate Cancer via ER Stress-Activated PERK Signaling Pathway.

Mol Cancer Ther 2020 01 17;19(1):101-111. Epub 2019 Sep 17.

The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.

Metastatic castration-resistant prostate cancer (CRPC) is currently incurable. Cancer growth and progression is intimately affected by its interaction with host microenvironment. Cotargeting of the stroma and prostate cancer is therefore an emerging therapeutic strategy for metastatic CRPC. Cancer-induced osteoclastogenesis is known to contribute to CRPC bone metastasis. This study is to extend pharmacologic value of our synthesized LCC03, a derivative of 5-(2',4'-difluorophenyl)-salicylanilide that has previously testified for its osteoclastogenesis activity, by exploring its additional cytotoxic properties and underlying mechanism in CRPC cells. LCC03 was chemically synthesized and examined for cell growth inhibition in a serial of CRPC cell lines. We demonstrated that LCC03 dose-dependently suppressed proliferation and retarded cell-cycle progression in CRPC cells. The classical autophagy features, including autophagosome formation and LC3-II conversion, were dramatically shown in LCC03-treated CRPC cells, and it was associated with the suppressed AKT/mTOR signaling pathways, a major negative regulator of autophagy. Moreover, an expanded morphology of the endoplasmic reticulum (ER), increased expression of the ER stress markers GRP78 and PERK, and eIF2α phosphorylation were observed. Blockage of autophagy and PERK pathways using small molecule inhibitors or shRNA knockdown reversed LCC03-induced autophagy and cell death, thus indicating that the PERK-eIF2α pathway contributed to the LCC03-induced autophagy. Furthermore, treatment of tumor-bearing mice with intraperitoneal administered LCC03 suppressed the growth of CRPC xenografts in mouse bone without systemic toxicity. The dual action of 5-(2',4'-difluorophenyl)-salicylanilide on targeting both the osteoclasts and the tumor cells strongly indicates that LCC03 is a promising anticancer candidate for preventing and treating metastatic CRPC.
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http://dx.doi.org/10.1158/1535-7163.MCT-19-0387DOI Listing
January 2020

A Circulating Tumor Cell-RNA Assay for Assessment of Androgen Receptor Signaling Inhibitor Sensitivity in Metastatic Castration-Resistant Prostate Cancer.

Theranostics 2019 13;9(10):2812-2826. Epub 2019 Apr 13.

Urologic Oncology Program and Uro-Oncology Research Laboratories, Cedars-Sinai Medical Center, Los Angeles, California, USA.

: Our objective was to develop a circulating tumor cell (CTC)-RNA assay for characterizing clinically relevant RNA signatures for the assessment of androgen receptor signaling inhibitor (ARSI) sensitivity in metastatic castration-resistant prostate cancer (mCRPC) patients. : We developed the NanoVelcro CTC-RNA assay by combining the Thermoresponsive (TR)-NanoVelcro CTC purification system with the NanoString nCounter platform for cellular purification and RNA analysis. Based on the well-validated, tissue-based Prostate Cancer Classification System (PCS), we focus on the most aggressive and ARSI-resistant PCS subtype, i.e., PCS1, for CTC analysis. We applied a rigorous bioinformatic process to develop the CTC-PCS1 panel that consists of prostate cancer (PCa) CTC-specific RNA signature with minimal expression in background white blood cells (WBCs). We validated the NanoVelcro CTC-RNA assay and the CTC-PCS1 panel with well-characterized PCa cell lines to demonstrate the sensitivity and dynamic range of the assay, as well as the specificity of the PCS1 Z score (the likelihood estimate of the PCS1 subtype) for identifying PCS1 subtype and ARSI resistance. We then selected 31 blood samples from 23 PCa patients receiving ARSIs to test in our assay. The PCS1 Z scores of each sample were computed and compared with ARSI treatment sensitivity. : The validation studies using PCa cell line samples showed that the NanoVelcro CTC-RNA assay can detect the RNA transcripts in the CTC-PCS1 panel with high sensitivity and linearity in the dynamic range of 5-100 cells. We also showed that the genes in CTC-PCS1 panel are highly expressed in PCa cell lines and lowly expressed in background WBCs. Using the artificial CTC samples simulating the blood sample conditions, we further demonstrated that the CTC-PCS1 panel is highly specific in identifying PCS1-like samples, and the high PCS1 Z score is associated with ARSI resistance samples. In patient bloods, ARSI-resistant samples (ARSI-R, n=14) had significantly higher PCS1 Z scores as compared with ARSI-sensitive samples (ARSI-S, n=17) (Rank-sum test, P=0.003). In the analysis of 8 patients who were initially sensitive to ARSI (ARSI-S) and later developed resistance (ARSI-R), we found that the PCS1 Z score increased from the time of ARSI-S to the time of ARSI-R (Pairwise T-test, P=0.016). : Using our new methodology, we developed a first-in-class CTC-RNA assay and demonstrated the feasibility of transforming clinically-relevant tissue-based RNA profiling such as PCS into CTC tests. This approach allows for detecting RNA expression relevant to clinical drug resistance in a non-invasive fashion, which can facilitate patient-specific treatment selection and early detection of drug resistance, a goal in precision oncology.
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http://dx.doi.org/10.7150/thno.34485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6568173PMC
May 2020

Establishment and characterization of a prostate cancer cell line from a prostatectomy specimen for the study of cellular interaction.

Int J Cancer 2019 10 10;145(8):2249-2259. Epub 2019 May 10.

Uro-Oncology Research, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA.

Though human prostate cancer (PCa) heterogeneity can best be studied using multiple cell types isolated from clinical specimens, the difficulty of establishing cell lines from clinical tumors has hampered this approach. In this proof-of-concept study, we established a human PCa cell line from a prostatectomy surgical specimen without the need for retroviral transduction. In a previous report, we characterized the stromal cells derived from PCa specimens. Here, we characterized the epithelial cells isolated from the same tumors. Compared to the ease of establishing prostate stromal cell lines, prostatic epithelial cell lines are challenging. From three matched pairs of normal and tumor tissues, we established one new PCa cell line, HPE-15. We confirmed the origin of HPE-15 cells by short tandem repeat microsatellite polymorphism analysis. HPE-15 cells are androgen-insensitive and express marginal androgen receptor, prostate-specific antigen and prostate-specific membrane antigen proteins. HPE-15 expresses luminal epithelial markers of E-cadherin and cytokeratin 18, basal cell markers of cytokeratin 5 and p63 and neuroendocrine marker of chromogranin A. Interestingly, HPE-15 Cells exhibited no tumorigenicity in different strains of immune-deficient mice but can become tumorigenic through interaction with aggressive cancer cell types. HPE-15 cells can thus serve as an experimental model for the study of PCa progression, metastasis and tumor cell dormancy.
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http://dx.doi.org/10.1002/ijc.32370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6703920PMC
October 2019

Targeting Burkitt lymphoma with a tumor cell-specific heptamethine carbocyanine-cisplatin conjugate.

Cancer 2019 07 6;125(13):2222-2232. Epub 2019 Mar 6.

Department of Medicine, Uro-Oncology Research Program, Cedars-Sinai Medical Center, Los Angeles, California.

Background: Burkitt lymphoma is a fast-growing mature B cell malignancy, whose genetic hallmark is translocation and activation of the c-myc gene. Prompt multiagent immunochemotherapy regimens can have favorable outcomes, but prognosis is poor in refractory or relapsed disease. We previously identified a novel family of near-infrared heptamethine carbocyanine fluorescent dyes (HMCD or DZ) with tumor-homing properties via organic anion-transporting peptides. These membrane carriers have uptake in tumor cells but not normal cells in cell culture, mouse and dog tumor models, patient-derived xenografts, and perfused kidney cancers in human patients.

Methods: Here we report the cytotoxic effects of a synthesized conjugate of DZ with cisplatin (CIS) on B cell lymphoma CA46, Daudi, Namalwa, Raji, and Ramos cell lines in cell culture and in xenograft tumor formation. Impaired mitochondrial membrane permeability was examined as the mechanism of DZ-CIS-induced lymphoma cell death.

Results: The new conjugate, DZ-CIS, is cytotoxic against Burkitt lymphoma cell lines and tumor models. DZ-CIS retains tumor-homing properties to mitochondrial and lysosomal compartments, does not accumulate in normal cells and tissues, and has no nephrotoxicity in mice. DZ-CIS accumulated in Burkitt lymphoma cells and tumors induces apoptosis and retards tumor cell growth in culture and xenograft tumor growth in mice.

Conclusion: DZ-CIS downregulated c-myc and overcame CIS resistance in myc-driven TP53-mutated aggressive B cell Burkitt lymphoma. We propose that DZ-CIS could be used to treat relapsed/refractory aggressive Burkitt lymphomas.
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http://dx.doi.org/10.1002/cncr.32033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6618854PMC
July 2019

Regulatory signaling network in the tumor microenvironment of prostate cancer bone and visceral organ metastases and the development of novel therapeutics.

Asian J Urol 2019 Jan 28;6(1):65-81. Epub 2018 Nov 28.

Uro-Oncology Research, Department of Medicine and Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

This article describes cell signaling network of metastatic prostate cancer (PCa) to bone and visceral organs in the context of tumor microenvironment and for the development of novel therapeutics. The article focuses on our recent progress in the understanding of: 1) The plasticity and dynamics of tumor-stroma interaction; 2) The significance of epigenetic reprogramming in conferring cancer growth, invasion and metastasis; 3) New insights on altered junctional communication affecting PCa bone and brain metastases; 4) Novel strategies to overcome therapeutic resistance to hormonal antagonists and chemotherapy; 5) Genetic-based therapy to co-target tumor and bone stroma; 6) PCa-bone-immune cell interaction and TBX2-WNTprotein signaling in bone metastasis; 7) The roles of monoamine oxidase and reactive oxygen species in PCa growth and bone metastasis; and 8) Characterization of imprinting cluster of microRNA, in tumor-stroma interaction. This article provides new approaches and insights of PCa metastases with emphasis on basic science and potential for clinical translation. This article referenced the details of the various approaches and discoveries described herein in peer-reviewed publications. We dedicate this article in our fond memory of Dr. Donald S. Coffey who taught us the spirit of sharing and the importance of focusing basic science discoveries toward translational medicine.
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http://dx.doi.org/10.1016/j.ajur.2018.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6363607PMC
January 2019

Regulatory signaling network in the tumor microenvironment of prostate cancer bone and visceral organ metastases and the development of novel therapeutics.

Asian J Urol 2019 Jan 28;6(1):65-81. Epub 2018 Nov 28.

Uro-Oncology Research, Department of Medicine and Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

This article describes cell signaling network of metastatic prostate cancer (PCa) to bone and visceral organs in the context of tumor microenvironment and for the development of novel therapeutics. The article focuses on our recent progress in the understanding of: 1) The plasticity and dynamics of tumor-stroma interaction; 2) The significance of epigenetic reprogramming in conferring cancer growth, invasion and metastasis; 3) New insights on altered junctional communication affecting PCa bone and brain metastases; 4) Novel strategies to overcome therapeutic resistance to hormonal antagonists and chemotherapy; 5) Genetic-based therapy to co-target tumor and bone stroma; 6) PCa-bone-immune cell interaction and TBX2-WNTprotein signaling in bone metastasis; 7) The roles of monoamine oxidase and reactive oxygen species in PCa growth and bone metastasis; and 8) Characterization of imprinting cluster of microRNA, in tumor-stroma interaction. This article provides new approaches and insights of PCa metastases with emphasis on basic science and potential for clinical translation. This article referenced the details of the various approaches and discoveries described herein in peer-reviewed publications. We dedicate this article in our fond memory of Dr. Donald S. Coffey who taught us the spirit of sharing and the importance of focusing basic science discoveries toward translational medicine.
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http://dx.doi.org/10.1016/j.ajur.2018.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6363607PMC
January 2019

ONECUT2 is a targetable master regulator of lethal prostate cancer that suppresses the androgen axis.

Nat Med 2018 12 26;24(12):1887-1898. Epub 2018 Nov 26.

Division of Cancer Biology and Therapeutics, Departments of Surgery & Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Treatment of prostate cancer (PC) by androgen suppression promotes the emergence of aggressive variants that are androgen receptor (AR) independent. Here we identify the transcription factor ONECUT2 (OC2) as a master regulator of AR networks in metastatic castration-resistant prostate cancer (mCRPC). OC2 acts as a survival factor in mCRPC models, suppresses the AR transcriptional program by direct regulation of AR target genes and the AR licensing factor FOXA1, and activates genes associated with neural differentiation and progression to lethal disease. OC2 appears active in a substantial subset of human prostate adenocarcinoma and neuroendocrine tumors. Inhibition of OC2 by a newly identified small molecule suppresses metastasis in mice. These findings suggest that OC2 displaces AR-dependent growth and survival mechanisms in many cases where AR remains expressed, but where its activity is bypassed. OC2 is also a potential drug target in the metastatic phase of aggressive PC.
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http://dx.doi.org/10.1038/s41591-018-0241-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6614557PMC
December 2018

Emerin Deregulation Links Nuclear Shape Instability to Metastatic Potential.

Cancer Res 2018 11 28;78(21):6086-6097. Epub 2018 Aug 28.

Division of Cancer Biology and Therapeutics, Department of Surgery and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California.

Abnormalities in nuclear shape are a well-known feature of cancer, but their contribution to malignant progression remains poorly understood. Here, we show that depletion of the cytoskeletal regulator, Diaphanous-related formin 3 (DIAPH3), or the nuclear membrane-associated proteins, lamin A/C, in prostate and breast cancer cells, induces nuclear shape instability, with a corresponding gain in malignant properties, including secretion of extracellular vesicles that contain genomic material. This transformation is characterized by a reduction and/or mislocalization of the inner nuclear membrane protein, emerin. Consistent with this, depletion of emerin evokes nuclear shape instability and promotes metastasis. By visualizing emerin localization, evidence for nuclear shape instability was observed in cultured tumor cells, in experimental models of prostate cancer, in human prostate cancer tissues, and in circulating tumor cells from patients with metastatic disease. Quantitation of emerin mislocalization discriminated cancer from benign tissue and correlated with disease progression in a prostate cancer cohort. Taken together, these results identify emerin as a mediator of nuclear shape stability in cancer and show that destabilization of emerin can promote metastasis. This study identifies a novel mechanism integrating the control of nuclear structure with the metastatic phenotype, and our inclusion of two types of human specimens (cancer tissues and circulating tumor cells) demonstrates direct relevance to human cancer. http://cancerres.aacrjournals.org/content/canres/78/21/6086/F1.large.jpg .
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http://dx.doi.org/10.1158/0008-5472.CAN-18-0608DOI Listing
November 2018

R1 Regulates Prostate Tumor Growth and Progression By Transcriptional Suppression of the E3 Ligase HUWE1 to Stabilize c-Myc.

Mol Cancer Res 2018 12 24;16(12):1940-1951. Epub 2018 Jul 24.

Depatment of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California.

Prostate cancer is a prevalent public health problem, especially because noncutaneous advanced malignant forms significantly affect the lifespan and quality of life of men worldwide. New therapeutic targets and approaches are urgently needed. The current study reports elevated expression of R1 (CDCA7L/RAM2/JPO2), a c-Myc-interacting protein and transcription factor, in human prostate cancer tissue specimens. In a clinical cohort, high R1 expression is associated with disease recurrence and decreased patient survival. Overexpression and knockdown of R1 in human prostate cancer cells indicate that R1 induces cell proliferation and colony formation. Moreover, silencing R1 dramatically reduces the growth of prostate tumor xenografts in mice. Mechanistically, R1 increases c-Myc protein stability by inhibiting ubiquitination and proteolysis through transcriptional suppression of , a c-Myc-targeting E3 ligase, via direct interaction with a binding element in the promoter. Moreover, transcriptional repression is supported by a negative coexpression correlation between and in a prostate cancer clinical dataset. Collectively, these findings, for the first time, characterize the contribution of R1 to prostate cancer pathogenesis. IMPLICATIONS: These findings provide evidence that R1 is a novel regulator of prostate tumor growth by stabilizing c-Myc protein, meriting further investigation of its therapeutic and prognostic potential.
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http://dx.doi.org/10.1158/1541-7786.MCR-16-0346DOI Listing
December 2018

Modulation of cabozantinib efficacy by the prostate tumor microenvironment.

Oncotarget 2017 Oct 23;8(50):87891-87902. Epub 2017 Sep 23.

Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.

The tumor microenvironment (TME) is increasingly recognized as the arbiter of metastatic progression and drug resistance in advanced prostate cancer (PCa). Cabozantinib is a potent tyrosine kinase inhibitor (TKI) with reported biological activity in the PCa epithelia, but failed to provide an overall survival benefit in phase 3 clinical trials. However, the promising biologic efficacy of the drug in early trials warranted a better understanding of the mechanism of action, with the goal of improving patient selection for TKI-based therapy such as cabozantinib. We found a 100-fold lower cabozantinib IC in macrophages, PCa associated fibroblasts, and bone marrow fibroblasts compared to PCa epithelia. In PCa mouse models, pre-treatment with cabozantinib potentiated osseous and visceral tumor engraftment, suggesting a pro-tumorigenic host response to the drug. We further found that the host effects of cabozantinib impacted bone turnover, but not necessarily tumor expansion. Cabozantinib affected M1 macrophage polarization in mice. Analogously, circulating monocytes from PCa patients treated with cabozantinib, demonstrated a striking correlation of monocyte reprograming with therapeutic bone responsivity, to support patient selection at early stages of treatment. Thus, a re-evaluation of TKI-based therapeutic strategies in PCa can be considered for suitable patient populations based on TME responses.
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http://dx.doi.org/10.18632/oncotarget.21248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5675680PMC
October 2017

Whole-genome and Transcriptome Sequencing of Prostate Cancer Identify New Genetic Alterations Driving Disease Progression.

Eur Urol 2018 Mar 18;73(3):322-339. Epub 2017 Sep 18.

Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, China. Electronic address:

Background: Global disparities in prostate cancer (PCa) incidence highlight the urgent need to identify genomic abnormalities in prostate tumors in different ethnic populations including Asian men.

Objective: To systematically explore the genomic complexity and define disease-driven genetic alterations in PCa.

Design, Setting, And Participants: The study sequenced whole-genome and transcriptome of tumor-benign paired tissues from 65 treatment-naive Chinese PCa patients. Subsequent targeted deep sequencing of 293 PCa-relevant genes was performed in another cohort of 145 prostate tumors.

Outcome Measurements And Statistical Analysis: The genomic alteration landscape in PCa was analyzed using an integrated computational pipeline. Relationships with PCa progression and survival were analyzed using nonparametric test, log-rank, and multivariable Cox regression analyses.

Results And Limitations: We demonstrated an association of high frequency of CHD1 deletion with a low rate of TMPRSS2-ERG fusion and relatively high percentage of mutations in androgen receptor upstream activator genes in Chinese patients. We identified five putative clustered deleted tumor suppressor genes and provided experimental and clinical evidence that PCDH9, deleted/loss in approximately 23% of tumors, functions as a novel tumor suppressor gene with prognostic potential in PCa. Furthermore, axon guidance pathway genes were frequently deregulated, including gain/amplification of PLXNA1 gene in approximately 17% of tumors. Functional and clinical data analyses showed that increased expression of PLXNA1 promoted prostate tumor growth and independently predicted prostate tumor biochemical recurrence, metastasis, and poor survival in multi-institutional cohorts of patients with PCa. A limitation of this study is that other genetic alterations were not experimentally investigated.

Conclusions: There are shared and salient genetic characteristics of PCa in Chinese and Caucasian men. Novel genetic alterations in PCDH9 and PLXNA1 were associated with disease progression.

Patient Summary: We reported the first large-scale and comprehensive genomic data of prostate cancer from Asian population. Identification of these genetic alterations may help advance prostate cancer diagnosis, prognosis, and treatment.
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http://dx.doi.org/10.1016/j.eururo.2017.08.027DOI Listing
March 2018

Reactive oxygen species-mediated switching expression of MMP-3 in stromal fibroblasts and cancer cells during prostate cancer progression.

Sci Rep 2017 08 22;7(1):9065. Epub 2017 Aug 22.

The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.

Studies on the aberrant control of extracellular matrices (ECMs) have mainly focused on the role of malignant cells but less on that of stromal fibroblasts during cancer development. Herein, by using paired normal and prostate cancer-associated stromal fibroblasts (CAFs) derived from a coculture cell model and clinical patient samples, we demonstrated that although CAFs promoted prostate cancer growth, matrix metalloproteinase-3 (MMP-3) was lower in CAFs but elevated in prostate cancer cells relative to their normal counterparts. Furthermore, hydrogen peroxide was characterized as the central modulator for altered MMP-3 expression in prostate cancer cells and CAFs, but through different regulatory mechanisms. Treatment of CAFs but not prostate cancer cells with hydrogen peroxide directly inhibited mmp-3 promoter activity with concomitant nuclear translocation of nuclear factor-κB (NF-κB), indicating that NF-κB is the downstream pathway for the transcriptional repression of MMP-3 in CAFs. Hydrogen peroxide reduced thrombospondin 2 (an MMP-3 suppressor) expression in prostate cancer cells by upregulating microRNA-128. To the best of our knowledge, this is the first study to demonstrate the crucial role of reactive oxygen species in the switching expression of MMP-3 in stromal fibroblasts and prostate cancer cells during tumor progression, clarifying how the tumor microenvironment modulates ECM homeostasis control.
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http://dx.doi.org/10.1038/s41598-017-08835-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5567216PMC
August 2017

Upregulation of minichromosome maintenance complex component 3 during epithelial-to-mesenchymal transition in human prostate cancer.

Oncotarget 2017 Jun;8(24):39209-39217

Department of Chemistry & Biochemistry, Florida State University, Tallahassee, FL, United States of America.

Metastasis is often associated with epithelial-to-mesenchymal transition (EMT). To understand the molecular mechanisms of this process, we conducted proteomic analysis of androgen-repressed cancer of the prostate (ARCaP), an experimental model of metastatic human prostate cancer. The protein signatures of epithelial (ARCaPE) and mesenchymal (ARCaPM) cells were consistent with their phenotypes. Importantly, the expression of mini-chromosome maintenance 3 (MCM3) protein, a crucial subunit of DNA helicase, was significantly higher in ARCaPM cells than that of ARCaPE cells. This increased MCM3 protein expression level was verified using Western blot analysis of the ARCaP cell lineages. Furthermore, immunohistochemical analysis of MCM3 protein levels in human prostate tissue specimens showed elevated expression in bone metastasis and advanced human prostate cancer tissue samples. Subcutaneous injection experiments using ARCaPE and ARCaPM cells in a mouse model also revealed increased MCM3 protein levels in mesenchymal-derived tumors. This study identifies MCM3 as an upregulated molecule in mesenchymal phenotype of human prostate cancer cells and advanced human prostate cancer specimens, suggesting MCM3 may be a new potential drug target for prostate cancer treatment.
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http://dx.doi.org/10.18632/oncotarget.16835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5503607PMC
June 2017

MAOA-Dependent Activation of Shh-IL6-RANKL Signaling Network Promotes Prostate Cancer Metastasis by Engaging Tumor-Stromal Cell Interactions.

Cancer Cell 2017 03;31(3):368-382

Uro-Oncology Research Program, Samuel Oschin Comprehensive Cancer Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. Electronic address:

Metastasis is a predominant cause of death for prostate cancer (PCa) patients; however, the underlying mechanisms are poorly understood. We report that monoamine oxidase A (MAOA) is a clinically and functionally important mediator of PCa bone and visceral metastases, activating paracrine Shh signaling in tumor-stromal interactions. MAOA provides tumor cell growth advantages in the bone microenvironment by stimulating interleukin-6 (IL6) release from osteoblasts, and triggers skeletal colonization by activating osteoclastogenesis through osteoblast production of RANKL and IL6. MAOA inhibitor treatment effectively reduces metastasis and prolongs mouse survival by disengaging the Shh-IL6-RANKL signaling network in stromal cells in the tumor microenvironment. These findings provide a rationale for targeting MAOA and its associated molecules to treat PCa metastasis.
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http://dx.doi.org/10.1016/j.ccell.2017.02.003DOI Listing
March 2017

Bone Metastasis of Prostate Cancer Can Be Therapeutically Targeted at the TBX2-WNT Signaling Axis.

Cancer Res 2017 03 20;77(6):1331-1344. Epub 2017 Jan 20.

Uro-Oncology Research Program, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.

Identification of factors that mediate visceral and bone metastatic spread and subsequent bone remodeling events is highly relevant to successful therapeutic intervention in advanced human prostate cancer. TBX2, a T-box family transcription factor that negatively regulates cell-cycle inhibitor p21, plays critical roles during embryonic development, and recent studies have highlighted its role in cancer. Here, we report that TBX2 is overexpressed in human prostate cancer specimens and bone metastases from xenograft mouse models of human prostate cancer. Blocking endogenous TBX2 expression in PC3 and ARCaP prostate cancer cell models using a dominant-negative construct resulted in decreased tumor cell proliferation, colony formation, and invasion Blocking endogenous TBX2 in human prostate cancer mouse xenografts decreased invasion and abrogation of bone and soft tissue metastasis. Furthermore, blocking endogenous TBX2 in prostate cancer cells dramatically reduced bone-colonizing capability through reduced tumor cell growth and bone remodeling in an intratibial mouse model. TBX2 acted in by promoting transcription of the canonical WNT () promoter. Genetically rescuing WNT3A levels in prostate cancer cells with endogenously blocked TBX2 partially restored the TBX2-induced prostate cancer metastatic capability in mice. Conversely, WNT3A-neutralizing antibodies or WNT antagonist SFRP-2 blocked TBX2-induced invasion. Our findings highlight TBX2 as a novel therapeutic target upstream of WNT3A, where WNT3A antagonists could be novel agents for the treatment of metastasis and for skeletal complications in prostate cancer patients. .
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http://dx.doi.org/10.1158/0008-5472.CAN-16-0497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5783646PMC
March 2017

Keratin 13 expression reprograms bone and brain metastases of human prostate cancer cells.

Oncotarget 2016 Dec;7(51):84645-84657

Uro-Oncology Research Program, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Lethal progression of prostate cancer metastasis can be improved by developing animal models that recapitulate the clinical conditions. We report here that cytokeratin 13 (KRT13), an intermediate filament protein, plays a directive role in prostate cancer bone, brain, and soft tissue metastases. KRT13 expression was elevated in bone, brain, and soft tissue metastatic prostate cancer cell lines and in primary and metastatic clinical prostate, lung, and breast cancer specimens. When KRT13 expression was determined at a single cell level in primary tumor tissues of 44 prostate cancer cases, KRT13 level predicted bone metastasis and the overall survival of prostate cancer patients. Genetically enforced KRT13 expression in human prostate cancer cell lines drove metastases toward mouse bone, brain and soft tissues through a RANKL-independent mechanism, as KRT13 altered the expression of genes associated with EMT, stemness, neuroendocrine/neuromimicry, osteomimicry, development, and extracellular matrices, but not receptor activator NF-κB ligand (RANKL) signaling networks in prostate cancer cells. Our results suggest new inhibitors targeting RANKL-independent pathways should be developed for the treatment of prostate cancer bone and soft tissue metastases.
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http://dx.doi.org/10.18632/oncotarget.13175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5356688PMC
December 2016

Applications of circulating tumor cells for prostate cancer.

Asian J Urol 2016 Oct 14;3(4):254-259. Epub 2016 Sep 14.

Urologic Oncology Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

One of the major challenges that clinicians face is in the difficulties of accurately monitoring disease progression. Prostate cancer is among these diseases and greatly affects the health of men globally. Circulating tumor cells (CTCs) are a rare population of cancer cells that have shed from the primary tumor and entered the peripheral circulation. Not until recently, clinical applications of CTCs have been limited to using enumeration as a prognostic tool in Oncology. However, advances in emerging CTC technologies point toward new applications that could revolutionize the field of prostate cancer. It is now possible to study CTCs as components of a liquid biopsy based on morphological phenotypes, biochemical analyses, and genomic profiling. These advances allow us to gain insight into the heterogeneity and dynamics of cancer biology and to further study the mechanisms behind the evolution of therapeutic resistance. These recent developments utilizing CTCs for clinical applications will greatly impact the future of prostate cancer research and pave the way towards personalized care for men.
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http://dx.doi.org/10.1016/j.ajur.2016.09.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5730870PMC
October 2016

Cultured circulating tumor cells and their derived xenografts for personalized oncology.

Asian J Urol 2016 Oct 25;3(4):240-253. Epub 2016 Aug 25.

Uro-Oncology Research, Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Recent cancer research has demonstrated the existence of circulating tumor cells (CTCs) in cancer patient's blood. Once identified, CTC biomarkers will be invaluable tools for clinical diagnosis, prognosis and treatment. In this review, we propose culture as a rational strategy for large scale amplification of the limited numbers of CTCs from a patient sample, to derive enough CTCs for accurate and reproducible characterization of the biophysical, biochemical, gene expressional and behavioral properties of the harvested cells. Because of tumor cell heterogeneity, it is important to amplify all the CTCs in a blood sample for a comprehensive understanding of their role in cancer metastasis. By analyzing critical steps and technical issues in CTC culture, we developed a cost-effective and reproducible protocol directly culturing whole peripheral blood mononuclear cells, relying on an assumed survival advantage in CTCs and CTC-like cells over the normal cells to amplify this specified cluster of cancer cells.
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http://dx.doi.org/10.1016/j.ajur.2016.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5730836PMC
October 2016

Biology and therapy of urological cancer metastasis.

Asian J Urol 2016 Oct 23;3(4):167-169. Epub 2016 Sep 23.

Uro-Oncology Research, Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

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http://dx.doi.org/10.1016/j.ajur.2016.09.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5730865PMC
October 2016

Combined cell surface carbonic anhydrase 9 and CD147 antigens enable high-efficiency capture of circulating tumor cells in clear cell renal cell carcinoma patients.

Oncotarget 2016 Sep;7(37):59877-59891

Department of Urology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.

Circulating tumor cells (CTCs) have emerged as promising tools for noninvasive cancer detection and prognosis. Most conventional approaches for capturing CTCs use an EpCAM-based enrichment strategy, which does not work well in cancers that show low or no expression of EpCAM, such as renal cell carcinoma (RCC). In this study, we developed a new set of cell surface markers including CA9 and CD147 as alternative CTC-capture antigens specifically designed for RCC patients. We showed that the expression of both CA9 and CD147 was prevalent in a RCC patient cohort (n=70) by immunohistochemical analysis, with both molecules in combination covering 97.1% of cases. The NanoVelcro platform combined with CA9-/CD147-capture antibodies demonstrated significantly higher efficiency for capturing both CTC-mimicking renal cancer cells and RCC CTCs in peripheral blood, compared to the conventional EpCAM-based method. Using immunofluorescence cytological validation at the single-cell level, we were able to identify bona fide CTCs in RCC patient blood following the well-accepted criteria in our CTC-capture system. We further demonstrated a significant association of CTC numbers as well as the CTC expression status of Vimentin, a mesenchymal marker, with disease progression, including pathologic features and clinical staging. These results provide new insights into developing novel, effective targets/approaches for capturing CTCs, making CTCs a valuable tool for improved cancer detection, prognosis and treatment in RCC.
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http://dx.doi.org/10.18632/oncotarget.10979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5312355PMC
September 2016

Combined cell surface carbonic anhydrase 9 and CD147 antigens enable high-efficiency capture of circulating tumor cells in clear cell renal cell carcinoma patients.

Oncotarget 2016 Sep;7(37):59877-59891

Department of Urology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.

Circulating tumor cells (CTCs) have emerged as promising tools for noninvasive cancer detection and prognosis. Most conventional approaches for capturing CTCs use an EpCAM-based enrichment strategy, which does not work well in cancers that show low or no expression of EpCAM, such as renal cell carcinoma (RCC). In this study, we developed a new set of cell surface markers including CA9 and CD147 as alternative CTC-capture antigens specifically designed for RCC patients. We showed that the expression of both CA9 and CD147 was prevalent in a RCC patient cohort (n=70) by immunohistochemical analysis, with both molecules in combination covering 97.1% of cases. The NanoVelcro platform combined with CA9-/CD147-capture antibodies demonstrated significantly higher efficiency for capturing both CTC-mimicking renal cancer cells and RCC CTCs in peripheral blood, compared to the conventional EpCAM-based method. Using immunofluorescence cytological validation at the single-cell level, we were able to identify bona fide CTCs in RCC patient blood following the well-accepted criteria in our CTC-capture system. We further demonstrated a significant association of CTC numbers as well as the CTC expression status of Vimentin, a mesenchymal marker, with disease progression, including pathologic features and clinical staging. These results provide new insights into developing novel, effective targets/approaches for capturing CTCs, making CTCs a valuable tool for improved cancer detection, prognosis and treatment in RCC.
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http://dx.doi.org/10.18632/oncotarget.10979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5312355PMC
September 2016

Improving Therapeutic Potential of Farnesylthiosalicylic Acid: Tumor Specific Delivery via Conjugation with Heptamethine Cyanine Dye.

Mol Pharm 2017 01 16;14(1):1-13. Epub 2016 Dec 16.

Uro-Oncology Research Program, Department of Medicine, Cedars-Sinai Medical Center , Los Angeles, California 90048, United States.

The RAS and mTOR inhibitor S-trans-trans-farnesylthiosalicylic acid (FTS) is a promising anticancer agent with moderate potency, currently undergoing clinical trials as a chemotherapeutic agent. FTS has displayed its potential against a variety of cancers including endocrine resistant breast cancer. However, the poor pharmacokinetics profile attributed to its high hydrophobicity is a major hindrance for its continued advancement in clinic. One of the ways to improve its therapeutic potential would be to enhance its bioavailability to cancer tissue by developing a method for targeted delivery. In the current study, FTS was conjugated with the cancer-targeting heptamethine cyanine dye 5 to form the FTS-dye conjugate 11. The efficiency of tumor targeting properties of conjugate 11 against cancer cell growth and mTOR inhibition was evaluated in vitro in comparison with parent FTS. Cancer targeting of 11 in a live mouse model of MCF7 xenografts was demonstrated with noninvasive, near-infrared fluorescence (NIRF) imaging. The results from our studies clearly suggest that the bioavailability of FTS is indeed improved as indicated by log P values and cancer cell uptake. The FTS-dye conjugate 11 displayed higher potency (IC = 16.8 ± 0.5 μM) than parent FTS (IC = ∼51.3 ± 1.8 μM) and inhibited mTOR activity in the cancer cells at a lower concentration (12.5 μM). The conjugate 11 was shown to be specifically accumulated in tumors as observed by in vivo NIRF imaging, organ distribution, and ex vivo tumor histology along with cellular level confocal microscopy. In conclusion, the conjugation of FTS with cancer-targeting heptamethine cyanine dye improved its pharmacological profile.
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http://dx.doi.org/10.1021/acs.molpharmaceut.5b00906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5815365PMC
January 2017

SREBP-2 promotes stem cell-like properties and metastasis by transcriptional activation of c-Myc in prostate cancer.

Oncotarget 2016 Mar;7(11):12869-84

Uro-Oncology Research Program, Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

Sterol regulatory element-binding protein-2 (SREBP-2) transcription factor mainly controls cholesterol biosynthesis and homeostasis in normal cells. The role of SREBP-2 in lethal prostate cancer (PCa) progression remains to be elucidated. Here, we showed that expression of SREBP-2 was elevated in advanced pathologic grade and metastatic PCa and significantly associated with poor clinical outcomes. Biofunctional analyses demonstrated that SREBP-2 induced PCa cell proliferation, invasion and migration. Furthermore, overexpression of SREBP-2 increased the PCa stem cell population, prostasphere-forming ability and tumor-initiating capability, whereas genetic silencing of SREBP-2 inhibited PCa cell growth, stemness, and xenograft tumor growth and metastasis. Clinical and mechanistic data showed that SREBP-2 was positively correlated with c-Myc and induced c-Myc activation by directly interacting with an SREBP-2-binding element in the 5'-flanking c-Myc promoter region to drive stemness and metastasis. Collectively, these clinical and experimental results reveal a novel role of SREBP-2 in the induction of a stem cell-like phenotype and PCa metastasis, which sheds light on translational potential by targeting SREBP-2 as a promising therapeutic approach in PCa.
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http://dx.doi.org/10.18632/oncotarget.7331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4914327PMC
March 2016