Publications by authors named "Sunyi Lee"

26 Publications

  • Page 1 of 1

Advanced Xenograft Model with Cotransplantation of Patient-Derived Organoids and Endothelial Colony-Forming Cells for Precision Medicine.

J Oncol 2021 13;2021:9994535. Epub 2021 Jul 13.

College of Pharmacy, Duksung Women's University, Seoul 01369, Republic of Korea.

Preclinical evaluation models have been developed for precision medicine, with patient-derived xenograft models (PDXs) and patient-derived organoids (PDOs) attracting increasing attention. However, each of these models has application limitations. In this study, an advanced xenograft model was established and used for drug screening. PDO and endothelial colony-forming cells (ECFCs) were cotransplanted in NRGA mice (PDOXwE) to prepare the model, which could also be subcultured in Balb/c nude mice. Our DNA sequencing analysis and immunohistochemistry results indicated that PDOXwE maintained patient genetic information and tumor heterogeneity. Moreover, the model enhanced tumor growth more than the PDO-bearing xenograft model (PDOX). The PDO, PDOXwE, and clinical data were also compared in the liver metastasis of a colorectal cancer patient, demonstrating that the chemosensitivity of PDO and PDOXwE coincided with the clinical data. These results suggest that PDOXwE is an improvement of PDOX and is suitable as an evaluation model for precision medicine.
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http://dx.doi.org/10.1155/2021/9994535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8294990PMC
July 2021

[Corrigendum] Cryptotanshinone inhibits IgE‑mediated degranulation through inhibition of spleen tyrosine kinase and tyrosine‑protein kinase phosphorylation in mast cells.

Mol Med Rep 2021 Sep 19;24(3). Epub 2021 Jul 19.

Department of Biological Science, Sookmyung Women's University, Seoul 04310, Republic of Korea.

Following the publication of the above article, an interested reader drew to the authors' attention that they had mentioned that activated PKCδ phosphorylates IKKβ in order that IKKβ is relocated to the plasma membrane, resulting in the induction of mast cell degranulation; however, four references the authors had included did not seem to support this statement. The authors have re-examined their paper, and realized that the four references the reader mentioned were indeed cited incorrectly, and wish to rectify this error through revising the third paragraph in the Discussion section, the References section, and an associated figure (Fig. 6C) in order to avoid any further misunderstandings on the part of the readership. First, the authors wish to revise the wording of the third and fourth paragraphs of the Discussion, as featured on pp. 1101-1102, to the following (changed text is indicated in bold): 'We showed that CRT exerts anti-AD effect through inhibition of the mast cell degranulation in mast cells. Upon IgE/antigen stimulation, the immunoreceptor tyrosine-based activation motif (ITAM) region of FcεRI receptor which is on the mast cell surface is phosphorylated and the initial signalling protein kinases Lyn and Syk are recruited to the ITAM (28,29). Then, the activated Lyn and Syk leads to phosphorylation of the transmembrane adaptor linker for activation of T cells (LAT). Phosphorylated LAT which is a scaffold for multimolecular signalling complexes and activates PLCγ through phosphorylation. The activated PLCγ hydrolyses phosphatidylinositol biphosphate (PIP2) to generate second signalling molecules IP3 and DAG, which activate PKCs including PKCδ to induce the mast cell degranulation (30,31). On the other hand, cross-linking of FcεRI also activates IKKβ, which moves to the lipid raft fractions and phosphorylates synaptosomal-associated protein 23 (SNAP-23) leading to degranulation (7). Since PKCδ phosphorylates IKKα, but not IKKβ (32), it is not likely that two signalling pathways are directly connected. In this study, novel function of CRT on phosphorylations of Lyn/Syk kinases in mast cells is elucidated for the first time. Furthermore, it is likely that this inhibitory effect of CRT on Lyn/Syk kinases negatively affected activities of their downstream signalling molecules including PLCγ, PKCδ, and IKKβ, which leads to decrease in mast cell degranulation by CRT treatment. Besides the inhibitory effect of CRT on mast cell degranulation, here we provide additional evidence that CRT exerts anti-AD effects through inactivation of MAPK and NF‑κB. It has been reported that CRT regulates the activities of MAPK and NF‑κB in various cell types. In rhabdomyosarcoma, hepatoma, and breast carcinoma, CRT activates MAPK p38/JNK and suppresses ERK1/2, followed by caspase-independent apoptosis (10,33,34). In chronic myeloid leukaemia cells, CRT enhances TNF‑α-induced apoptosis through the activation of MAPK p38 (35). In smooth muscle cells, CRT exerts anti-migration/invasion effect as it inhibits TNF‑α/NF‑κB signalling pathway (36).' Secondly, the authors wish to make the following changes to the Reference list: New references 30-32 have been inserted to the list, as follows: 30. Ozawa K, Szallasi Z, Kazanietz MG, Blumberg PM, Mischak H, Mushinski JF and Beaven MA: Ca-dependent and Ca-independent isozymes of protein kinase C mediate exocytosis in antigen-stimulated rat basophilic RBL-2H3 cell. J Biol Chem 268: 1749-1756, 1993. 31. Cho SH, Woo CH, Yoon SB and Kim JH: Protein kinase Cδ functions downstream of Ca mobilization in FcεRI signaling to degranulation in mast cells. J Allergy Clin Immunol 114: 1085-1092, 2004. 32. Yamaguchi T, Miki Y and Yoshida K: Protein kinase Cδ activates IκB-kinase α to induce the p53 tumor suppressor in response to oxidative stress. Cell Signal 19: 2088-2097, 2007. The addition of these new references means that the former references 30-33 have been accordingly renumbered to references 33-36. Finally, the authors have revised Fig. 6C, as it appeared on p. 1102, in order to assist the understanding of the readers, and the corrected version of Fig. 6 appears on the next page. All these corrections have been approved by all the authors, with the exception of the first author, Sumiyasuren Buyanravjikh, who is no longer uncontactable. The authors regret that these errors were included in the paper, even though they did not substantially alter any of the major conclusions reported in the study, are grateful to the Editor for allowing them this opportunity to publish a Corrigendum, and apologize to the readership for any inconvenience caused. [the original article was published in 18: 1095‑1193, 2018; DOI: 10.3892/mmr.2018.9042].
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http://dx.doi.org/10.3892/mmr.2021.12283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8299195PMC
September 2021

Estrogen Aggravates Tumor Growth in a Diffuse Gastric Cancer Xenograft Model.

Pathol Oncol Res 2021 16;27:622733. Epub 2021 Apr 16.

Duksung Innovative Drug Center, Duksung Women's University, Seoul, Korea.

Gastric cancer has the fifth-highest incidence rate and is the third leading cause of cancer-related deaths worldwide. The incidence of gastric cancer is higher in men than in women, but for the diffuse types of gastric cancer, the trend is opposite. Estrogen is considered the prime culprit behind these differences. Nevertheless, the action of estrogen in gastric cancers remains unclear. In this study, we investigated the effect of estrogen on diffuse-type gastric cancer. Human female diffuse gastric cancer SNU-16 cells were transplanted into male and female mice to analyze the effect of endogenous estrogen on tumor growth. Furthermore, the effect of exogenous estrogen was evaluated in ovariectomized mice. Expressed genes were compared between female and male xenograft models using RNA sequencing analysis. Furthermore, human gene expression omnibus databases were utilized to examine the effect of our target genes on overall survival. SNU-16-derived tumor growth was faster in female mice than in male mice. In total RNA sequencing, interferon gamma receptor 2 (), IQ motif containing E (), transient receptor potential cation channel subfamily M member 4 (), and structure-specific endonuclease subunit SLX4 () were found. These genes could be associated with the tumor growth in female diffuse-type gastric cancer which was affected by endogenous estrogen. In an ovariectomized gastric cancer xenograft model, exogenous estrogen promoted tumor growth. Especially, our results indicated that estrogen induced G protein-coupled estrogen receptor expression in these mice. These results suggest that estrogen aggravates tumor progression in female diffuse gastric cancer.
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http://dx.doi.org/10.3389/pore.2021.622733DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262185PMC
April 2021

Potentiating activities of chrysin in the therapeutic efficacy of 5-fluorouracil in gastric cancer cells.

Oncol Lett 2021 Jan 11;21(1):24. Epub 2020 Nov 11.

Duksung Innovative Drug Center, Duksung Women's University, Seoul 01369, Republic of Korea.

The incidence and mortality rates of gastric cancer rank among the highest five of all cancer types worldwide. The chemotherapeutic agent 5-fluorouracil (5-FU) is the gold standard for treating gastric cancer, but its efficacy is limited due to high rates of resistance. To improve the therapeutic efficacy of 5-FU and overcome its resistance, the synergistic effect of chrysin with 5-FU was investigated and its mechanism was elucidated. Chrysin was co-administered with 5-FU in AGS cells and 5-FU-resistant AGS cells (AGS/FR). Cytotoxicity was investigated using MTT assay, followed by calculating the combination index (CI). Several biomarkers were detected using western blotting analysis. Apoptosis and cell cycle distribution were measured by flow cytometry. The combination of chrysin and 5-FU significantly increased cytotoxicity more than chrysin or 5-FU alone. 5-FU induced apoptosis through p53-p21 activity, while chrysin arrested the cell cycle in the G2/M phase. The combination of chrysin and 5-FU showed an anticancer effect via S phase arrest. The results indicated that chrysin and 5-FU exhibited anticancer properties via different pathways. Furthermore, the present study found that chrysin enhanced the chemotherapeutic effect of 5-FU in AGS/FR cells. In the resistant cells, the combination of chrysin and 5-FU improved the anticancer effect via G2/M phase arrest. These findings indicated that chrysin potentiated the chemotherapeutic effect of 5-FU in gastric cancer AGS and AGS/FR cells via cell cycle arrest. Therefore, chrysin may be used to treat gastric cancers that have become resistant to 5-FU.
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http://dx.doi.org/10.3892/ol.2020.12285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7681229PMC
January 2021

Deubiquitinase USP47-stabilized splicing factor IK regulates the splicing of pre-mRNA.

Cell Death Discov 2020 4;6:34. Epub 2020 May 4.

1Department of Biological Sciences, Sookmyung Women's University, Seoul, 04310 Korea.

IK depletion leads to an aberrant mitotic entry because of chromosomal misalignment through the enhancement of Aurora B activity at the interphase. Here, we demonstrate that IK, a spliceosomal component, plays a crucial role in the proper splicing of the pre-mRNA among other genes related with the DNA Damage Response (DDR). Intron 1 in the pre-mRNA, having lengths <200 bp, was not spliced in the IK-depleted cells and led to a deficiency of the ATM protein. Subsequently, the IK depletion-induced ATM protein deficiency impaired the ability to repair the damaged DNA. Because the absence of SMU1 results in IK degradation, the mechanism underlying IK degradation was exploited. IK was ubiquitinated in the absence of SMU1 and then subjected to proteolysis through the 26S proteasome. To prevent the proteolytic degradation of IK, a deubiquitinating enzyme, USP47, directly interacted with IK and stabilized it through deubiquitination. Collectively, our results suggest that IK is required for proper splicing of the pre-mRNA and USP47 contributes toward the stabilization of IK.
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http://dx.doi.org/10.1038/s41420-020-0268-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198525PMC
May 2020

Monofacet-Selective Cavitation within Solid-State Silica-Nanoconfinement toward Janus Iron Oxide Nanocube.

J Am Chem Soc 2018 11 30;140(45):15176-15180. Epub 2018 Oct 30.

National Creative Research Initiative Center for Nanospace-Confined Chemical Reactions (NCCR) and Department of Chemistry , Pohang University of Science and Technology (POSTECH) , Pohang 37673 , South Korea.

Here, a highly selective solid-state nanocrystal conversion strategy is developed toward concave iron oxide (FeO) nanocube with an open-mouthed cavity engraved exclusively on a single face. The strategy is based on a novel heat-induced nanospace-confined domino-type migration of Fe ions from the SiO-FeO interface toward the surrounding silica shell and concomitant self-limiting nanoscale phase-transition to the Fe-silicate form. Equipped with the chemically unique cavity, the produced Janus-type concave iron oxide nanocube was further functionalized with controllable density of catalytic Pt-nanocrystals exclusively on concave sites and utilized as a highly diffusive catalytic Janus nanoswimmer for the efficient degradation of pollutant-dyes in water.
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http://dx.doi.org/10.1021/jacs.8b09869DOI Listing
November 2018

C1q/TNF-α-Related Protein 1 (CTRP1) Maintains Blood Pressure Under Dehydration Conditions.

Circ Res 2018 08;123(5):e5-e19

Department of Biological Sciences (K.H.Y., S.B., J.-S.L., M.-S.L., Y.Y.).

Rationale: Circulating CTRP1 (C1q/TNF-α [tumor necrosis factor-α]-related protein 1) levels are increased in hypertensive patients compared with those in healthy subjects. Nonetheless, little is known about the molecular and physiological function of CTRP1 in blood pressure (BP) regulation.

Objective: To investigate the physiological/pathophysiological role of CTRP1 in BP regulation.

Methods And Results: CTRP1 production was increased to maintain normotension under dehydration conditions, and this function was impaired in inducible CTRP1 KO (knockout) mice (CTRP1 ). The increase in CTRP1 under dehydration conditions was mediated by glucocorticoids, and the antagonist mifepristone prevented the increase in CTRP1 and attenuated BP recovery. Treatment with a synthetic glucocorticoid increased the transcription, translation, and secretion of CTRP1 from skeletal muscle cells. Functionally, CTRP1 increases BP through the stimulation of the AT1R (Ang II [angiotensin II] receptor 1)-Rho (Ras homolog gene family)/ROCK (Rho kinase)-signaling pathway to induce vasoconstriction. CTRP1 promoted AT1R plasma membrane trafficking through phosphorylation of AKT and AKT substrate of 160 kDa (AS160). In addition, the administration of an AT1R blocker, losartan, recovered the hypertensive phenotype of CTRP1 TG (transgenic) mice.

Conclusions: For the first time, we provide evidence that CTRP1 contributes to the regulation of BP homeostasis by preventing dehydration-induced hypotension.
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http://dx.doi.org/10.1161/CIRCRESAHA.118.312871DOI Listing
August 2018

Cryptotanshinone inhibits IgE‑mediated degranulation through inhibition of spleen tyrosine kinase and tyrosine‑protein kinase phosphorylation in mast cells.

Mol Med Rep 2018 Jul 22;18(1):1095-1103. Epub 2018 May 22.

Department of Biological Science, Sookmyung Women's University, Seoul 04310, Republic of Korea.

Atopic dermatitis (AD) is a type of chronic skin inflammation and one of the most common relapsing allergic diseases, which presents with a severe rash and itchy skin lesions. The pathogenesis of AD is primarily associated with hyper‑activated mast cells, which makes them an effective treatment target. After cross‑linking the antigen/immunoglobulin (Ig) E complex binds to its high affinity receptor FcεRl on the surface of mast cells. The cells subsequently secrete excessive pro‑inflammatory mediators, including histamine and cytokines, which lead to pruritus and immune cell infiltration in the skin lesions. The present study screened natural compounds that have an inhibitory effect on IgE/antigen‑mediated secretory activity. It was revealed that cryptotanshinone (CRT), a natural compound extracted from Salvia miltiorrhiza Bunge, had inhibitory effects on the IgE/antigen complex. The underlying mechanism by which CRT exerted an anti‑allergy/inflammatory function was investigated using rat basophilic leukaemia (RBL) cells for degranulation assays and a 1‑chloro‑2,4‑dinitrobenzene (DNCB)‑induced AD Balb/c mouse model for in vivo study. CRT effectively mitigated the secretion of pro‑inflammatory cytokines, including tumor necrosis factor‑α and interleukin 1β, as well as immune cell infiltration into skin lesions in a mouse model of AD‑like skin disease induced by dinitrochlorobenzene. The inhibitory effect of CRT on IgE‑mediated mast cell degranulation was mediated by the inhibition of tyrosine kinase‑dependent degranulation signalling pathways involving spleen tyrosine kinase and Lyn. The present study revealed CRT as an inhibitor of mast cell degranulation. Therefore, CRT may be considered for development as a therapeutic drug to treat IgE‑mediated skin diseases.
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http://dx.doi.org/10.3892/mmr.2018.9042DOI Listing
July 2018

Oncoprotein CIP2A promotes the disassembly of primary cilia and inhibits glycolytic metabolism.

EMBO Rep 2018 05 28;19(5). Epub 2018 Feb 28.

Division of Biological Sciences, Department of Life Systems, Research Center for Women's Disease, Sookmyung Women's University, Seoul, Korea

In most mammalian cells, the primary cilium is a microtubule-enriched protrusion of the plasma membrane and acts as a key coordinator of signaling pathways during development and tissue homeostasis. The primary cilium is generated from the basal body, and cancerous inhibitor of protein phosphatase 2A (CIP2A), the overexpression of which stabilizes c-MYC to support the malignant growth of tumor cells, is localized in the centrosome. Here, we show that CIP2A overexpression induces primary cilia disassembly through the activation of Aurora A kinase, and CIP2A depletion increases ciliated cells and cilia length in retinal pigment epithelium (RPE1) cells. CIP2A depletion also shifts metabolism toward the glycolytic pathway by altering the expression of metabolic genes related to glycolysis. However, glycolytic activation in CIP2A-depleted cells does not depend on cilia assembly, even though enhanced cilia assembly alone activates glycolytic metabolism. Collectively, these data suggest that CIP2A promotes primary cilia disassembly and that CIP2A depletion induces metabolic reprogramming independent of primary cilia.
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http://dx.doi.org/10.15252/embr.201745144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5934771PMC
May 2018

Eupatolide inhibits the TGF-β1-induced migration of breast cancer cells via downregulation of SMAD3 phosphorylation and transcriptional repression of ALK5.

Oncol Lett 2017 Nov 15;14(5):6031-6039. Epub 2017 Sep 15.

Department of Biological Science, Sookmyung Women's University, Seoul 04310, Republic of Korea.

The epithelial-mesenchymal transition (EMT) is a hallmark of cancer metastasis, and the associated molecular signaling pathways are regarded as therapeutic targets for cancer treatment. Thus, suppressing EMT with a natural chemical compound may be of therapeutic benefit. Eupatolide is a natural chemical compound extracted from the medicinal plant , which is used in Eastern Asia to treat bronchitis, disorders of the digestive system and inflammation. Besides the anti-inflammatory function of eupatolide, the present study found that eupatolide suppressed the migration and invasion of breast cancer cells, which was associated with the downregulation of vimentin in MDA-MB-231 cells and the upregulation of E-cadherin in MCF-7 cells. Treatment with eupatolide also significantly inhibited the migration and invasion of breast cancer cells that had been stimulated with transforming growth factor-β1 (TGF-β1). Eupatolide also suppressed TGF-β1-induced EMT via downregulation of mothers against decapentaplegic homolog 3 (SMAD3) phosphorylation and transcriptional repression of TGF-β receptor 1 (ALK5). In addition to this canonical pathway, the non-canonical protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) pathways were also inhibited by eupatolide treatment. In summary, the results suggest that eupatolide suppresses the migration and invasion of breast cancer cells by blocking the canonical ALK5-SMAD3 signaling pathway and the non-canonical ERK and AKT signaling pathways.
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http://dx.doi.org/10.3892/ol.2017.6957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5661662PMC
November 2017

Von Hippel-Lindau regulates interleukin-32β stability in ovarian cancer cells.

Oncotarget 2017 Sep 17;8(41):69833-69846. Epub 2017 Jul 17.

Department of Biological Sciences, Sookmyung Women's University, Seoul, Republic of Korea.

Hypoxia-induced interleukin-32β (IL-32β) shifts the metabolic program to the enhanced glycolytic pathway. In the present study, the underlying mechanism by which hypoxia-induced IL-32β stability is regulated was investigated in ovarian cancer cells. IL-32β expression increased under hypoxic conditions in ovarian cancer cells as it did in breast cancer cells. The amount of IL-32β was regulated by post-translational control rather than by transcriptional activation. Under normoxic conditions, IL-32β was continuously eliminated through ubiquitin-dependent degradation by the von-Hippel Lindau (VHL) E3 ligase complex. Oxygen deficiency or reactive oxygen species (ROS) disrupted the interaction between IL-32β and VHL, leading to the accumulation of the cytokine. The fact that IL-32β is regulated by the energy-consuming ubiquitination system implies that it plays an important role in oxidative stress. We found that IL-32β reduced protein kinase Cδ (PKCδ)-induced apoptosis under oxidative stress. This implies that the hypoxia- and ROS-stabilized IL-32β contributes to sustain survival against PKCδ-induced apoptosis.
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http://dx.doi.org/10.18632/oncotarget.19311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5642520PMC
September 2017

Neuronatin Is Associated with an Anti-Inflammatory Role in the White Adipose Tissue.

J Microbiol Biotechnol 2017 Jun;27(6):1180-1188

Department of Biological Sciences, Sookmyung Women's University, Seoul 04310, Republic of Korea.

Neuronatin (NNAT) is known to regulate ion channels during brain development and plays a role in maintaining the structure of the nervous system. A previous in silico analysis showed that was overexpressed in the adipose tissue of an obese rodent model relative to the wild type. Therefore, the aim of the present study was to investigate the function of in the adipose tissue. Because obesity is known to systemically induce low-grade inflammation, the expression level was examined in the adipose tissue obtained from C57BL/6 mice administered lipopolysaccharide (LPS). Unexpectedly, the expression level decreased in the white adipose tissue after LPS administration. To determine the role of NNAT in inflammation, 3T3-L1 cells overexpressing were treated with LPS. The level of the p65 subunit of nuclear factor-kappa B (NF-κB) and the activity of NF-κB luciferase decreased following LPS treatment. These results indicate that NNAT plays an anti-inflammatory role in the adipose tissue.
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http://dx.doi.org/10.4014/jmb.1702.02049DOI Listing
June 2017

Circulating CTRP1 Levels in Type 2 Diabetes and Their Association with FGF21.

Int J Endocrinol 2016 23;2016:5479627. Epub 2016 May 23.

Department of Biological Sciences, Sookmyung Women's University, 04310 Seoul, Republic of Korea.

The goal of this study was to investigate whether circulating C1q/TNF-α-related protein 1 (CTRP1) levels are associated with diabetes. In addition, relationships between CTRP1 and other diabetes-related cytokines were elucidated, including adiponectin and fibroblast growth factor 21 (FGF21). A total of 178 subjects (78 men and 100 women) aged 29-70 years (mean age, 46.1 years) were randomly selected. The sera from a normal glucose tolerance group (n = 68) and a prediabetes/type 2 diabetes group (n = 110) were collected; then, circulating levels of CTRP1, adiponectin, and FGF21 were determined via enzyme-linked immunosorbent assay in all sera. Subjects with either prediabetes or diabetes exhibited higher circulating CTRP1 levels than healthy subjects. Sera analysis revealed that CTRP1 was positively correlated with age, body mass index, fasting blood glucose, and circulating FGF21 levels. However, CTRP1 was negatively correlated with total cholesterol and total circulating adiponectin levels in univariate analysis. In addition, multivariate analysis found that CTRP1 was independently associated with age, fasting blood glucose, and circulating FGF21 levels. CTRP1 was correlated with homeostasis model assessment-β (HOMA-β), but no correlation was observed with HOMA-insulin resistance. In conclusion, circulating CTRP1 levels are increased in subjects with type 2 diabetes and are positively associated with circulating FGF21 levels.
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http://dx.doi.org/10.1155/2016/5479627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4893584PMC
June 2016

Patient derived mutation W257G of PPP2R1A enhances cancer cell migration through SRC-JNK-c-Jun pathway.

Sci Rep 2016 06 7;6:27391. Epub 2016 Jun 7.

Department of Biological Sciences, Sookmyung Women's University, Seoul 140-742, Republic of Korea.

Mutation of PPP2R1A has been observed at high frequency in endometrial serous carcinomas but at low frequency in ovarian clear cell carcinoma. However, the biological role of mutation of PPP2R1A in ovarian and endometrial cancer progression remains unclear. In this study, we found that PPP2R1A expression is elevated in high-grade primary tumor patients with papillary serous tumors of the ovary. To determine whether increased levels or mutation of PPP2R1A might contribute to cancer progression, the effects of overexpression or mutation of PPP2R1A on cell proliferation, migration, and PP2A phosphatase activity were investigated using ovarian and endometrial cancer cell lines. Among the mutations, PPP2R1A-W257G enhanced cell migration in vitro through activating SRC-JNK-c-Jun pathway. Overexpression of wild type (WT) PPP2R1A increased its binding ability with B56 regulatory subunits, whereas PPP2R1A-mutations lost the ability to bind to most B56 subunits except B56δ. Total PP2A activity and PPP2R1A-associated PP2Ac activity were significantly increased in cells overexpressing PPP2R1A-WT. In addition, overexpression of PPP2R1A-WT increased cell proliferation in vitro and tumor growth in vivo.
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http://dx.doi.org/10.1038/srep27391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4895347PMC
June 2016

Suppression of Adipocyte Differentiation by Foenumoside B from Lysimachia foenum-graecum Is Mediated by PPARγ Antagonism.

PLoS One 2016 13;11(5):e0155432. Epub 2016 May 13.

Department of Pharmacology, Gachon University School of Medicine, Incheon, Republic of Korea.

Lysimachia foenum-graecum extract (LFE) and its active component foenumoside B (FSB) have been shown to inhibit adipocyte differentiation, but their mechanisms were poorly defined. Here, we investigated the molecular mechanisms responsible for their anti-adipogenic effects. Both LFE and FSB inhibited the differentiation of 3T3-L1 preadipocytes induced by peroxisome proliferator-activated receptor-γ (PPARγ) agonists, accompanied by reductions in the expressions of the lipogenic genes aP2, CD36, and FAS. Moreover, LFE and FSB inhibited PPARγ transactivation activity with IC50s of 22.5 μg/ml and 7.63 μg/ml, respectively, and showed selectivity against PPARα and PPARδ. Rosiglitazone-induced interaction between PPARγ ligand binding domain (LBD) and coactivator SRC-1 was blocked by LFE or FSB, whereas reduced NCoR-1 binding to PPARγ by rosiglitazone was reversed in the presence of LFE or FSB. In vivo administration of LFE into either ob/ob mice or KKAy mice reduced body weights, and levels of PPARγ and C/EBPα in fat tissues. Furthermore, insulin resistance was ameliorated by LFE treatment, with reduced adipose tissue inflammation and hepatic steatosis. Thus, LFE and FSB were found to act as PPARγ antagonists that improve insulin sensitivity and metabolic profiles. We propose that LFE and its active component FSB offer a new therapeutic strategy for metabolic disorders including obesity and insulin resistance.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0155432PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4866755PMC
July 2017

IK-guided PP2A suppresses Aurora B activity in the interphase of tumor cells.

Cell Mol Life Sci 2016 09 23;73(17):3375-86. Epub 2016 Feb 23.

Division of Biological Sciences, Department of Life Systems, Research Center for Women's Disease, Sookmyung Women's University, Seoul, 140-742, Republic of Korea.

Aurora B activation is triggered at the mitotic entry and required for proper microtubule-kinetochore attachment at mitotic phase. Therefore, Aurora B should be in inactive form in interphase to prevent aberrant cell cycle progression. However, it is unclear how the inactivation of Aurora B is sustained during interphase. In this study, we find that IK depletion-induced mitotic arrest leads to G2 arrest by Aurora B inhibition, indicating that IK depletion enhances Aurora B activation before mitotic entry. IK binds to Aurora B, and colocalizes on the nuclear foci during interphase. Our data further show that IK inhibits Aurora B activation through recruiting PP2A into IK and Aurora B complex. It is thus believed that IK, as a scaffold protein, guides PP2A into Aurora B to suppress its activity in interphase until mitotic entry.
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http://dx.doi.org/10.1007/s00018-016-2162-9DOI Listing
September 2016

CTRP1 protects against diet-induced hyperglycemia by enhancing glycolysis and fatty acid oxidation.

J Nutr Biochem 2016 Jan 28;27:43-52. Epub 2015 Aug 28.

Department of Life Systems, Sookmyung Women's University, Seoul, Republic of Korea. Electronic address:

Complement-C1q/tumor necrosis factor-α related protein 1 (CTRP1) is a 35-kDa glycoprotein that is secreted from various tissues. Although CTRP1 is highly increased in patients with type II diabetes and obesity, the metabolic roles of CTRP1 remain largely unknown. To unveil the physiological roles of CTRP1 in vivo, CTRP1 transgenic (TG) mice were challenged by a high-fat diet (HFD) and a high-sucrose drink (HS). Homeostatic model assessment-estimated insulin resistance values were decreased in HFD- or HS-fed CTRP1 TG mice compared with wild-type control mice. In this context, CTRP1 stimulated glucose uptake through the glucose transporter GLUT4 translocation to the plasma membrane and also increased glucose consumption by stimulating glycolysis. To analyze the roles of CTRP1 in lipid metabolism, acetyl-CoA carboxylase (ACC) and hormone-sensitive lipase levels were determined in CTRP1 TG mice, and the effect of CTRP1 on fatty acid oxidation was assessed in C2C12 myotubes. CTRP1 was found to inhibit ACC by phosphorylation and to stimulate fatty acid oxidation in C2C12 myotubes. Taken together, CTRP1 performs active catabolic roles in vivo. Therefore, CTRP1 seems to perform a defensive function against nutritional challenges.
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http://dx.doi.org/10.1016/j.jnutbio.2015.08.018DOI Listing
January 2016

Combined Treatment of Herbal Mixture Extract H9 with Trastuzumab Enhances Anti-tumor Growth Effect.

J Microbiol Biotechnol 2015 Jul;25(7):1036-46

Department of Life Systems, Sookmyung Women's University, Seoul 140-742, Republic of Korea.

Extracts from Asian medicinal herbs are known to be successful therapeutic agents against cancer. In this study, the effects of three types of herbal extracts on anti-tumor growth were examined. Among the three types of herbal extracts, H9 showed stronger anti-tumor growth effects than H5 and H11 in vivo. To find the molecular mechanism by which H9 inhibited the proliferation of breast cancer cell lines, the levels of apoptotic markers were examined. Proapoptotic markers, including cleaved PARP and cleaved caspases 3 and 9, were increased, whereas the anti-apoptotic marker Bcl-2 was decreased by H9 treatment. Next, the combined effect of H9 with the chemotherapeutic drugs doxorubicin/cyclophosphamide (AC) on tumor growth was examined using 4T1-tumor-bearing mice. The combined treatment of H9 with AC did not show additive or synergetic anti-tumor growth effects. However, when tumor-bearing mice were co-treated with H9 and the targeted anti-tumor drug trastuzumab, a delay in tumor growth was observed. The combined treatment of H9 and trastuzumab caused an increase of natural killer (NK) cells and a decrease of myeloid-derived suppressor cells (MDSC). Taken together, H9 induces the apoptotic death of tumor cells while increasing anti-tumor immune activity through the enhancement of NK activity and diminishment of MDSC.
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http://dx.doi.org/10.4014/jmb.1501.01017DOI Listing
July 2015

Hypoxia-induced IL-32β increases glycolysis in breast cancer cells.

Cancer Lett 2015 Jan 6;356(2 Pt B):800-8. Epub 2014 Nov 6.

Department of Biosystems, Sookmyung Women's University, Seoul 140-742, Republic of Korea. Electronic address:

IL-32β is highly expressed and increases the migration and invasion of gastric, lung, and breast cancer cells. Since IL-32 enhances VEGF production under hypoxic conditions, whether IL-32β is regulated by hypoxia was examined. Hypoxic conditions and a mimetic chemical CoCl2 enhanced IL-32β production. When cells were treated with various inhibitors of ROS generation to prevent hypoxia-induced ROS function, IL-32β production was suppressed by both NADPH oxidase and mitochondrial ROS inhibitors. IL-32β translocated to the mitochondria under hypoxic conditions, where it was associated with mitochondrial biogenesis. Thus, whether hypoxia-induced IL-32β is associated with oxidative phosphorylation (OXPHOS) or glycolysis was examined. Glycolysis under aerobic and anaerobic conditions is impaired in IL-32β-depleted cells, and the hypoxia-induced IL-32β increased glycolysis through activation of lactate dehydrogenase. Src is also known to increase lactate dehydrogenase activity, and the hypoxia-induced IL-32β was found to stimulate Src activation by inhibiting the dephosphorylation of Src. These findings revealed that a hypoxia-ROS-IL-32β-Src-glycolysis pathway is associated with the regulation of cancer cell metabolism.
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http://dx.doi.org/10.1016/j.canlet.2014.10.030DOI Listing
January 2015

Depletion of IK causes mitotic arrest through aberrant regulation of mitotic kinases and phosphatases.

FEBS Lett 2014 Aug 1;588(17):2844-50. Epub 2014 Jul 1.

Research Center for Women's Disease, Department of Life Systems, Sookmyung Women's University, Seoul 140-742, Republic of Korea. Electronic address:

IK is known to inhibit the expression of major histocompatibility complex (MHC) class II antigen, but other cellular functions of IK remain to be uncovered. In this study, IK depletion caused misalignment of chromosomes through an increase in Aurora A and PLK1 phosphorylation, which was mediated by a decrease in PP1 and PP2A activities. On the other hand, the treatment of a dual inhibitor against CDK and Aurora kinases overrode IK depletion-induced mitotic arrest through the activation of phosphatase activity. These findings imply that IK is an essential protein for achieving correct mitotic progress through the regulation of mitotic kinases and phosphatases.
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http://dx.doi.org/10.1016/j.febslet.2014.06.046DOI Listing
August 2014

Cancerous inhibitor of protein phosphatase 2A (CIP2A) protein is involved in centrosome separation through the regulation of NIMA (never in mitosis gene A)-related kinase 2 (NEK2) protein activity.

J Biol Chem 2014 Jan 8;289(1):28-40. Epub 2013 Nov 8.

From the Research Center for Women's Disease, Department of Life Systems and.

Cancerous inhibitor of protein phosphatase 2A (CIP2A) is overexpressed in most human cancers and has been described as being involved in the progression of several human malignancies via the inhibition of protein phosphatase 2A (PP2A) activity toward c-Myc. However, with the exception of this role, the cellular function of CIP2A remains poorly understood. On the basis of yeast two-hybrid and coimmunoprecipitation assays, we demonstrate here that NIMA (never in mitosis gene A)-related kinase 2 (NEK2) is a binding partner for CIP2A. CIP2A exhibited dynamic changes in distribution, including the cytoplasm and centrosome, depending on the cell cycle stage. When CIP2A was depleted, centrosome separation and the mitotic spindle dynamics were impaired, resulting in the activation of spindle assembly checkpoint signaling and, ultimately, extension of the cell division time. Our data imply that CIP2A strongly interacts with NEK2 during G2/M phase, thereby enhancing NEK2 kinase activity to facilitate centrosome separation in a PP1- and PP2A-independent manner. In conclusion, CIP2A is involved in cell cycle progression through centrosome separation and mitotic spindle dynamics.
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http://dx.doi.org/10.1074/jbc.M113.507954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3879551PMC
January 2014

Interleukin-32β stimulates migration of MDA-MB-231 and MCF-7cells via the VEGF-STAT3 signaling pathway.

Cell Oncol (Dordr) 2013 Dec 10;36(6):493-503. Epub 2013 Oct 10.

Research Center for Women's Disease, Sookmyung Women's University, Seoul, 140-742, South Korea.

Background: IL-32 is known to play an important role in inflammatory and autoimmune disease responses. In addition to its role in these responses, IL-32 and its different isoforms have in recent years been implicated in the development of various cancers. As of yet, the role of IL-32 in breast cancer has remained largely unknown.

Results: By performing immunohistochemical assays on primary breast cancer samples, we found that the level of IL-32β expression was positively correlated with tumor size, number of lymph node metastases and tumor stage. In addition, we found that breast cancer-derived MDA-MB-231 cells exogenously expressing IL-32β exhibited increased migration and invasion capacities. These increased capacities were found to be associated with an increased expression of the epithelial mesenchymal transition (EMT) markers vimentin and Slug, the latter of which is responsible for the increase in vimentin transcription. To next investigate whether IL-32β enhances migration and invasion through a soluble factor, we determined the levels of several migration-stimulating ligands, and found that the production of VEGF was increased by IL-32β. In addition, we found that IL-32β-induced VEGF increased migration and invasion through STAT3 activation.

Conclusion: The IL-32β-VEGF-STAT3 pathway represents an additional pathway that mediates the migration and invasion of breast cancer cells under the conditions of normoxia and hypoxia.
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http://dx.doi.org/10.1007/s13402-013-0154-4DOI Listing
December 2013

Adiponectin deficiency suppresses lymphoma growth in mice by modulating NK cells, CD8 T cells, and myeloid-derived suppressor cells.

J Immunol 2013 May 25;190(9):4877-86. Epub 2013 Mar 25.

Research Center for Women's Disease, Department of Life Science, Sookmyung Women's University, Seoul 140-742, Republic of Korea.

Previously, we found that adiponectin (APN) suppresses IL-2-induced NK cell activation by downregulating the expression of the IFN-γ-inducible TNF-related apoptosis-inducing ligand and Fas ligand. Although the antitumor function of APN has been reported in several types of solid tumors, with few controversial results, no lymphoma studies have been conducted. In this study, we assessed the role of APN in immune cell function, including NK cells, CTLs, and myeloid-derived suppressor cells, in EL4 and B16F10 tumor-bearing APN knockout (KO) mice. We observed attenuated EL4 growth in the APNKO mice. Increased numbers of splenic NK cells and splenic CTLs were identified under naive conditions and EL4-challenged conditions, respectively. In APNKO mice, splenic NK cells showed enhanced cytotoxicity with and without IL-2 stimulation. Additionally, there were decreased levels of myeloid-derived suppressor cell accumulation in the EL4-bearing APNKO mice. Enforced MHC class I expression on B16F10 cells led to attenuated growth of these tumors in APNKO mice. Thus, our results suggest that EL4 regression in APNKO mice is not only due to an enhanced antitumor immune response but also to a high level of MHC class I expression.
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http://dx.doi.org/10.4049/jimmunol.1202487DOI Listing
May 2013

Herbal extract THI improves metabolic abnormality in mice fed a high-fat diet.

Nutr Res Pract 2011 Jun 21;5(3):198-204. Epub 2011 Jun 21.

Department of Biological Science, Sookmyung Women's University, Cheongpa-ro 47-gil 100, Yongsan-gu, Seoul 140-742, Korea.

Target herbal ingredient (THI) is an extract made from two herbs, Scutellariae Radix and Platycodi Radix. It has been developed as a treatment for metabolic diseases such as hyperlipidemia, atherosclerosis, and hypertension. One component of these two herbs has been reported to have anti-inflammatory, anti-hyperlipidemic, and anti-obesity activities. However, there have been no reports about the effects of the mixed extract of these two herbs on metabolic diseases. In this study, we investigated the metabolic effects of THI using a diet-induced obesity (DIO) mouse model. High-fat diet (HFD) mice were orally administered daily with 250 mg/kg of THI. After 10 weeks of treatment, the THI-administered HFD mice showed reduction of body weights and epididymal white adipose tissue weights as well as improved glucose tolerance. In addition, the level of total cholesterol in the serum was markedly reduced. To elucidate the molecular mechanism of the metabolic effects of THI in vitro, 3T3-L1 cells were treated with THI, after which the mRNA levels of adipogenic transcription factors, including C/EBPα and PPARγ, were measured. The results show that the expression of these two transcription factors was down regulated by THI in a dose-dependent manner. We also examined the combinatorial effects of THI and swimming exercise on metabolic status. THI administration simultaneously accompanied by swimming exercise had a synergistic effect on serum cholesterol levels. These findings suggest that THI could be developed as a supplement for improving metabolic status.
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http://dx.doi.org/10.4162/nrp.2011.5.3.198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3133751PMC
June 2011

IFITM6 expression is increased in macrophages of tumor-bearing mice.

Oncol Rep 2011 Feb 10;25(2):531-6. Epub 2010 Dec 10.

Department of Biological Science, Sookmyung Women's University, Seoul 140-742, Republic of Korea.

The family of interferon-induced transmembrane protein (IFITM) genes consists of IFITM1, 2, 3, 5, and 6. They encode cell surface proteins that modulate cell-cell adhesion and cell differentiation. In a previous study, we showed that IFITM1 is involved in the immune escape and metastasis of gastric cancer cells. In this study, we determined the difference in expression of IFITM family genes in tumor-bearing mice. IFITM1 and 6 were found to be significantly increased. IFITM6 gene expression was increased only in the spleen of tumor-bearing mice but not in the bone marrow, lymph node, or thymus. IFITM6 expression was induced in various macrophages, including splenic, thioglycollate-elicited, and bone marrow-derived macrophages, but not in T cells. Lipopolysaccharides (LPS) also increased IFITM6 expression 24 h after administration, and Toll-like receptor 1, 2, 3, 4, and 9 agonists stimulated IFITM6 expression. These findings imply that the increase in IFITM6 expression may be involved in macrophage functions of tumor-bearing mice.
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http://dx.doi.org/10.3892/or.2010.1092DOI Listing
February 2011
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