Publications by authors named "Jiyun Yoo"

43 Publications

Phytochemicals Targeting JAK-STAT Pathways in Inflammatory Bowel Disease: Insights from Animal Models.

Molecules 2021 May 10;26(9). Epub 2021 May 10.

Division of Applied Life Science (BK21), PMBBRC and Research Institute of Life Sciences, Gyeongsang National University, Jinju 52828, Korea.

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract that consists of Crohn's disease (CD) and ulcerative colitis (UC). Cytokines are thought to be key mediators of inflammation-mediated pathological processes of IBD. These cytokines play a crucial role through the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) signaling pathways. Several small molecules inhibiting JAK have been used in clinical trials, and one of them has been approved for IBD treatment. Many anti-inflammatory phytochemicals have been shown to have potential as new drugs for IBD treatment. This review describes the significance of the JAK-STAT pathway as a current therapeutic target for IBD and discusses the recent findings that phytochemicals can ameliorate disease symptoms by affecting the JAK-STAT pathway in vivo in IBD disease models. Thus, we suggest that phytochemicals modulating JAK-STAT pathways are potential candidates for developing new therapeutic drugs, alternative medicines, and nutraceutical agents for the treatment of IBD.
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http://dx.doi.org/10.3390/molecules26092824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126249PMC
May 2021

Apoptotic Effects of Anthocyanins from Are Enhanced by Augmented Enhancer of the Rudimentary Homolog (ERH) in Human Gastric Carcinoma MKN28 Cells.

Int J Mol Sci 2021 Mar 16;22(6). Epub 2021 Mar 16.

Department of Biochemistry, Dong-eui University College of Korean Medicine, Busan 47227, Korea.

Evidence suggests that augmented expression of a certain gene can influence the efficacy of targeted and conventional chemotherapies. Here, we tested whether the high expression of enhancer of the rudimentary homolog (ERH), which serves as a prognostic factor in some cancers, can influence the efficacy of anthocyanins isolated from fruits of , Meoru in Korea (AIMs) on human gastric cancer cells. The anticancer efficacy of AIMs was augmented in ERH-transfected MKN28 cells (E-MKN28 cells). Molecularly, ERH augmented AIM-induced caspase-dependent apoptosis by activating caspase-3 and -9. The ERH-augmented apoptotic effect was related to mitochondrial depolarization and inhibition of antiapoptotic proteins, XIAP, and Bcl-2. In addition, reactive oxygen species (ROS) generation was augmented in AIMs-treated E-MKN28 cells compared to AIMs-treated naïve MKN28 cells. In conclusion, ERH augmented AIM-induced caspase-dependent mitochondrial-related apoptosis in MKN28 cells. A decrease in expression of Bcl-2 and subsequent excessive ROS generation would be the mechanism for ERH-augmented mitochondrial-related apoptosis in AIMs-treated MKN28 cells. A decrease in expression of XIAP would be another mechanism for ERH-augmented caspase-dependent apoptosis in AIMs-treated MKN28 cells.
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http://dx.doi.org/10.3390/ijms22063030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002340PMC
March 2021

Cullin 3/KCTD5 Promotes the Ubiqutination of Rho Guanine Nucleotide Dissociation Inhibitor 1 and Regulates Its Stability.

J Microbiol Biotechnol 2020 Oct;30(10):1488-1494

Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea.

Rho guanine nucleotide dissociation inhibitor 1 (RhoGDI1) plays important roles in numerous cellular processes, including cell motility, adhesion, and proliferation, by regulating the activity of Rho GTPases. Its expression is altered in various human cancers and is associated with malignant progression. Here, we show that RhoGDI1 interacts with Cullin 3 (CUL3), a scaffold protein for E3 ubiquitin ligase complexes. Ectopic expression of CUL3 increases the ubiquitination of RhoGDI1. Furthermore, potassium channel tetramerization domain containing 5 (KCTD5) also binds to RhoGDI1 and increases its interaction with CUL3. Ectopic expression of KCTD5 increases the ubiquitination of RhoGDI1, whereas its knockdown by RNA interference has the opposite effect. Depletion of KCTD5 or expression of dominant-negative CUL3 (DN-CUL3) enhances the stability of RhoGDI1. Our findings reveal a previously unknown mechanism for controlling RhoGDI1 degradation that involves a CUL3/KCTD5 ubiquitin ligase complex.
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http://dx.doi.org/10.4014/jmb.2007.07033DOI Listing
October 2020

Bacterial type III effector protein HopQ inhibits melanoma motility through autophagic degradation of vimentin.

Cell Death Dis 2020 04 14;11(4):231. Epub 2020 Apr 14.

Environmental Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea.

Malignant melanoma is a fatal disease that rapidly spreads to the whole body. Treatments have limited efficiency owing to drug resistance and various side effects. Pseudomonas syringae pv. tomato (Pto) is a model bacterial pathogen capable of systemic infection in plants. Pto injects the effector protein HopQ into the plant cytosol via a type III secretion machinery and suppresses the host immunity. Intriguingly, host plant proteins regulated by HopQ are conserved even in humans and conferred in tumor metastasis. Nevertheless, the potential for HopQ to regulate human cancer metastasis was unknown. In this study, we addressed the suitability of HopQ as a possible drug against melanoma metastasis. In melanoma cells, overexpressed HopQ is phosphorylated and bound to 14-3-3 through its N-terminal domain, resulting in stronger interaction between HopQ and vimentin. The binding of HopQ to vimentin allowed for degradation of vimentin via p62-dependent selective autophagy. Attenuation of vimentin expression by HopQ inhibited melanoma motility and in vivo metastasis. These findings demonstrated that HopQ directly degraded vimentin in melanoma cells and could be applied to an inhibitor of melanoma metastasis.
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http://dx.doi.org/10.1038/s41419-020-2427-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156461PMC
April 2020

PRDX4 overexpression is associated with poor prognosis in gastric cancer.

Oncol Lett 2020 May 19;19(5):3522-3530. Epub 2020 Mar 19.

Department of Surgery, School of Medicine, Gyeongsang National University, Jinju, South Gyeongsang 52727, Republic of Korea.

Peroxiredoxin IV (PRDX4) is a multifunctional protein that is involved in cell protection against oxidative injury, regulation of cell proliferation, modulation of intracellular signaling, and the pathogenesis of tumors. We previously conducted a proteomic analysis to investigate tumor-specific protein expression in gastric cancer. The aim of the present study was to investigate whether PRDX4 could be a marker of poor prognosis in patients with gastric cancer. Immunohistochemistry was used to validate PRDX4 as a prognostic marker for gastric cancer. Short hairpin RNA (shRNA)-mediated knockdown of PRDX4 expression in AGS cells and MKN28 cells was used for functional studies, and PRDX4 overexpression in PRDX4-depleted cells was used for knock-in studies. Based on immunohistochemistry data, TNM stage and PRDX4 were independent prognostic factors in the Cox proportional hazard model (P<0.05). In the survival analysis, the PRDX4-overexpressing group demonstrated significantly worse survival than the PRDX4-underexpression group (P<0.01). , knockdown of PRDX4 expression by shRNA caused a significant decrease in cancer invasion. Conversely, overexpression of PRDX4 in PRDX4-depleted cancer cells promoted migration and invasion. By measuring the expression of EMT-related genes, we found that E-cadherin was increased in shPRDX4 cells compared with control shMKN28 cells, and snail and slug were decreased in shPRDX4-1 cells compared with sh-control cells. Furthermore, the expression levels of these genes could be recovered in rescue experiments. In conclusion, the results of the present study suggested that PRDX4 is a marker of poor prognosis in gastric cancer and that PRDX4 is associated with cancer cell migration and invasion via EMT.
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http://dx.doi.org/10.3892/ol.2020.11468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7114939PMC
May 2020

Cordycepin Resensitizes T24R2 Cisplatin-Resistant Human Bladder Cancer Cells to Cisplatin by Inactivating Ets-1 Dependent MDR1 Transcription.

Int J Mol Sci 2020 Mar 2;21(5). Epub 2020 Mar 2.

Division of Applied Life Science (BK21 Plus), Gyeongsang National University, Jinju 52828, Korea.

Tumor cell resistance to anti-cancer drugs is a major obstacle in tumor therapy. In this study, we investigated the mechanism of cordycepin-mediated resensitization to cisplatin in T24R2 cells, a T24-derived cell line. Treatment with cordycepin or cisplatin (2 μg/mL) alone failed to induce cell death in T24R2 cells, but combination treatment with these drugs significantly induced apoptosis through mitochondrial pathways, including depolarization of mitochondrial membranes, decrease in anti-apoptotic proteins Bcl-2, Bcl-xL, and Mcl-1, and increase in pro-apoptotic proteins Bak and Bax. High expression levels of MDR1 were the cause of cisplatin resistance in T24R2 cells, and cordycepin significantly reduced MDR1 expression through inhibition of MDR1 promoter activity. MDR1 promoter activity was dependent on transcription factor Ets-1 in T24R2 cells. Although correlation exists between MDR1 and Ets-1 expression in bladder cancer patients, active Ets-1, Thr38 phosphorylated form (pThr38), was critical to induce MDR1 expression. Cordycepin decreased pThr-38 Ets-1 levels and reduced MDR1 transcription, probably through its effects on PI3K signaling, inducing the resensitization of T24R2 cells to cisplatin. The results suggest that cordycepin effectively resensitizes cisplatin-resistant bladder cancer cells to cisplatin, thus serving as a potential strategy for treatment of cancer in patients with resistance to anti-cancer drugs.
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http://dx.doi.org/10.3390/ijms21051710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7084876PMC
March 2020

C5, A Cassaine Diterpenoid Amine, Induces Apoptosis via the Extrinsic Pathways in Human Lung Cancer Cells and Human Lymphoma Cells.

Int J Mol Sci 2020 Feb 14;21(4). Epub 2020 Feb 14.

Division of Life Science, College of Natural Sciences, Gyeongsang National University, Jinju 52828, Korea.

Apoptosis pathways in cells are classified into two pathways: the extrinsic pathway, mediated by binding of the ligand to a death receptor and the intrinsic pathway, mediated by mitochondria. Apoptosis is regulated by various proteins such as Bcl-2 (B-cell lymphoma 2) family and cellular FLICE (Fas-associated Death Domain Protein Interleukin-1β-converting enzyme)-inhibitory protein (c-FLIP), which have been reported to inhibit caspase-8 activity. In this study, it was found that C5 (3β-Acetyl-nor-erythrophlamide), a compound of cassaine diterpene amine from Erythrophleum fordii, induced cell apoptosis in a variety of types of cancer cells. Induction of apoptosis in cancer cells by C5 was inversely related to the level of Bcl-2 expression. Overexpression of Bcl-2 into cancer cells significantly decreased C5-induced apoptosis. It was also found that treatment of cancer cells with a caspase-8 inhibitor significantly suppressed C5-induced apoptosis; however, treatment with caspase-9 inhibitors did not affect C5-induced apoptosis, suggesting that C5 may induce apoptosis via the extrinsic pathway by activating caspase-8. It was confirmed that treatment with C5 alone induced an association of FADD with procaspase-8; however, overexpression of c-FLIP decreased C5-induced caspase-8 activation. In conclusion, C5 could be utilized as a new useful lead compound for the development of an anti-cancer agent that has the goal of apoptosis.
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http://dx.doi.org/10.3390/ijms21041298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072863PMC
February 2020

Chelidonine Induces Caspase-Dependent and Caspase-Independent Cell Death through G Arrest in the T98G Human Glioblastoma Cell Line.

Evid Based Complement Alternat Med 2019 26;2019:6318179. Epub 2019 May 26.

Division of Applied Life Science (BK21Plus), Gyeongsang National University, Jinju 660-701, Republic of Korea.

. (family Papaveraceae), commonly known as greater celandine or tetterwort, has been reported to have antibacterial and anticancer effects and chelidonine is known as a functional metabolite extracted from C.
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http://dx.doi.org/10.1155/2019/6318179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6556348PMC
May 2019

p38 Stabilizes Snail by Suppressing DYRK2-Mediated Phosphorylation That Is Required for GSK3β-βTrCP-Induced Snail Degradation.

Cancer Res 2019 08 17;79(16):4135-4148. Epub 2019 Jun 17.

Division of Applied Life Science (BK21 Plus), Research Institute of Life Sciences, Gyeongsang National University, Jinju, Korea.

Snail is a key regulator of epithelial-mesenchymal transition (EMT), which is a major step in tumor metastasis. Although the induction of Snail transcription precedes EMT, posttranslational regulation, especially phosphorylation of Snail, is critical for determining Snail protein levels or stability, subcellular localization, and the ability to induce EMT. To date, several kinases are known that enhance the stability of Snail by preventing its ubiquitination; however, the molecular mechanism(s) underlying this are still unclear. Here, we identified p38 MAPK as a crucial posttranslational regulator that enhances the stability of Snail. p38 directly phosphorylated Snail at Ser107, and this effectively suppressed DYRK2-mediated Ser104 phosphorylation, which is critical for GSK3β-dependent Snail phosphorylation and βTrCP-mediated Snail ubiquitination and degradation. Importantly, functional studies and analysis of clinical samples established a crucial role for the p38-Snail axis in regulating ovarian cancer EMT and metastasis. These results indicate the potential therapeutic value of targeting the p38-Snail axis in ovarian cancer. SIGNIFICANCE: These findings identify p38 MAPK as a novel regulator of Snail protein stability and potential therapeutic target in ovarian cancer.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-0049DOI Listing
August 2019

TTYH1 and TTYH2 Serve as LRRC8A-Independent Volume-Regulated Anion Channels in Cancer Cells.

Cells 2019 06 9;8(6). Epub 2019 Jun 9.

Center for Functional Connectomics, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea.

Volume-regulated anion channels (VRACs) are involved in cellular functions such as regulation of cell volume, proliferation, migration, and cell death. Although leucine-rich repeat-containing 8A (LRRC8A) has been characterized as a molecular component of VRACs, here we show that Drosophila melanogaster tweety homologue 1 and 2 (TTYH1 and TTYH2) are critical for VRAC currents in cancer cells. LRRC8A-independent VRAC currents were present in the gastric cancer cell line SNU-601, but almost completely absent in its cisplatin-resistant derivative SNU-601-R10 (R10). The VRAC current in R10 was partially restored by treatment with trichostatin A (TSA), a histone deacetylase inhibitor. Based on microarray expression profiling of these cells, we selected two chloride channels, TTYH1 and TTYH2, as VRAC candidates. VRAC currents were completely absent from TTYH1- and TTYH2-deficient SNU-601 cells, and were clearly restored by expression of TTYH1 or TTYH2. In addition, we examined the expression of TTYH1 or TTYH2 in several cancer cell lines and found that VRAC currents of these cells were abolished by gene silencing of TTYH1 or TTYH2. Taken together, our data clearly show that TTYH1 and TTYH2 can act as LRRC8A-independent VRACs, suggesting novel therapeutic approaches for VRACs in cancer cells.
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http://dx.doi.org/10.3390/cells8060562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628158PMC
June 2019

NDRG2 Sensitizes Myeloid Leukemia to Arsenic Trioxide via GSK3β-NDRG2-PP2A Complex Formation.

Cells 2019 05 22;8(5). Epub 2019 May 22.

Division of Applied Life Science (BK21 Plus), Gyeongsang National University, Jinju 52828, Korea.

N-Myc downstream-regulated gene 2 (NDRG2) was characterized as a tumor suppressor, inducing anti-metastatic and anti-proliferative effects in several tumor cells. However, NDRG2 functions on anticancer drug sensitivity, and its molecular mechanisms are yet to be fully investigated. In this study, we investigated the mechanism of NDRG2-induced sensitization to AsO in the U937 cell line, which is one of the most frequently used cells in the field of resistance to AsO. NDRG2-overexpressing U937 cells (U937-NDRG2) showed a higher sensitivity to AsO than mock control U937 cell (U937-Mock). The higher sensitivity to AsO in U937-NDRG2 was associated with Mcl-1 degradation through glycogen synthase kinase 3β (GSK3β) activation. Inhibitory phosphorylation of GSK3β was significantly reduced in U937-NDRG2, and the reduction was diminished by okadaic acid, a protein phosphatase inhibitor. NDRG2 mediated the interaction between GSK3β and protein phosphatase 2A (PP2A), inducing dephosphorylation of GSK3β at S9 by PP2A. Although the C-terminal deletion mutant of NDRG2 (ΔC NDRG2), which could not interact with PP2A, interacted with GSK3β, the mutant failed to dephosphorylate GSK3β at S9 and increased sensitivity to AsO. Our findings suggest that NDRG2 is a kind of adaptor protein mediating the interaction between GSK3β and PP2A, inducing GSK3β activation through dephosphorylation at S9 by PP2A, which increases sensitivity to AsO in U937 cells.
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http://dx.doi.org/10.3390/cells8050495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562968PMC
May 2019

Downregulation of CHIP promotes ovarian cancer metastasis by inducing Snail-mediated epithelial-mesenchymal transition.

Mol Oncol 2019 05 8;13(5):1280-1295. Epub 2019 Apr 8.

Division of Applied Life Science (BK21 Plus), Research Institute of Life Sciences, Gyeongsang National University, Jinju, Korea.

The epithelial-mesenchymal transition (EMT) plays a pivotal role in the conversion of early-stage tumors into invasive malignancies. The transcription factor Snail, an extremely unstable protein whose subcellular levels are regulated by many E3 ubiquitin ligases, promotes EMT as well as associated pathological characteristics including migration, invasion, and metastasis. Through yeast two-hybrid screening, we identified the carboxyl terminus of Hsc70-interacting protein (CHIP) as a novel Snail ubiquitin ligase that interacts with Snail to induce ubiquitin-mediated proteasomal degradation. Inhibition of CHIP expression increases Snail protein levels, induces EMT, and enhances in vitro migration and invasion as well as in vivo metastasis of ovarian cancer cells. In turn, Snail depletion abrogates all phenomena induced by CHIP depletion. Finally, Snail and CHIP expression is inversely correlated in ovarian tumor tissues. These findings establish the CHIP-Snail axis as a post-translational mechanism of EMT and cancer metastasis regulation.
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http://dx.doi.org/10.1002/1878-0261.12485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6487736PMC
May 2019

Calponin 3 Regulates Cell Invasion and Doxorubicin Resistance in Gastric Cancer.

Gastroenterol Res Pract 2019 18;2019:3024970. Epub 2019 Feb 18.

Division of Applied Life Science (BK21 Plus), Research Institute of Life Sciences, Gyeongsang National University, Jinju 52828, Republic of Korea.

Calponin 3 (CNN3) is an F-actin-binding protein that regulates actin cytoskeletal rearrangement. However, the role of CNN3 in cancer cell invasion and resistance to chemotherapeutic agents has not yet been investigated. The present study was undertaken to investigate whether CNN3 influences cancer-related phenotypes in gastric cancer. We demonstrate that CNN3 contributes to cell invasion and resistance to doxorubicin in gastric cancer. CNN3 expression was markedly elevated in highly invasive cancer cell lines compared to less invasive or noninvasive cancer cell lines. Depletion of CNN3 protein suppressed the invasive ability of gastric cancer cells. The highly invasive MKN-28 gastric cancer cells were more resistant to doxorubicin than the noninvasive MKN-45 cells; however, knockdown of CNN3 expression in MKN-28 cells resensitized them to doxorubicin treatment. Taken together, our results suggest that CNN3 plays a key role in invasiveness and doxorubicin resistance in gastric cancer cells.
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http://dx.doi.org/10.1155/2019/3024970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6398029PMC
February 2019

NDRG2 contributes to cisplatin sensitivity through modulation of BAK-to-Mcl-1 ratio.

Cell Death Dis 2018 01 18;9(2):30. Epub 2018 Jan 18.

Division of Applied Life Science (BK21 Plus), Gyeongsang National University, Jinju, 52828, Republic of Korea.

The downregulation of N-Myc downstream-regulated gene 2 (NDRG2) is known to be associated with the progression and poor prognosis of several cancers. Sensitivity to anti-cancer may be associated with a good prognosis in cancer patients, and NDRG2, which is induced by p53, sensitizes the cells to chemotherapy. However, the unique function of NDRG2 as an inducer of apoptosis under chemotreatment has not been sufficiently studied. In this study, we investigated the role of NDRG2 in chemo-sensitivity, focusing on cisplatin in U937 histiocytic lymphoma, which has the loss-of-functional mutation in p53. NDRG2 promoted the sensitivity to cisplatin through the modulation of the BAK-to-Mcl-1 ratio. The degradation of Mcl-1 and increase in BAK were mediated by JNK activation and the eIF2α/p-eIF2α pathway, respectively, which depended on PKR activation in NDRG2-overexpressed U937 (U937-NDRG2) cells. NOX5 was highly expressed in U937-NDRG2 cells and contributed to ROS production after cisplatin treatment. ROS scavenging or NOX5-knockdown successfully inhibited the sensitivity of U937-NDRG2 cells to cisplatin. Taken together, these findings indicate that NDRG2 contributed to the increased sensitivity to ciplatin through the modulation of Bak-to-Mcl-1 ratio regulated by NOX5-ROS-PKR pathway; therefore, we suggest that NDRG2 may be a molecular target for improving the efficacy of drug treatment in cancer patients.
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http://dx.doi.org/10.1038/s41419-017-0184-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833685PMC
January 2018

Protein phosphatase 1B dephosphorylates Rho guanine nucleotide dissociation inhibitor 1 and suppresses cancer cell migration and invasion.

Cancer Lett 2018 03 5;417:141-151. Epub 2018 Jan 5.

Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea; Department of Biomolecular Science, University of Science and Technology (UST), Daejeon, Republic of Korea. Electronic address:

Rho GTPases control a wide range of cellular processes, and their deregulation is associated with promotion of an aggressive and metastatic tumor phenotype in human cancers. Rho guanine nucleotide dissociation inhibitor 1 (RhoGDI1) plays a key role in regulating the activity of Rho GTPases. However, the underlying mechanisms are still unclear. In this study, we show that protein phosphatase 1B (PPM1B) interacts with RhoGDI1 and functions as its phosphatase. Ectopic expression of PPM1B results in dephosphorylation of RhoGDI1 and, thereby, abates the activation of RhoA, Rac1 and CDC42 by epidermal growth factor (EGF). PPM1B overexpression in Hs578T and SKBR3 human breast cancer cells decreases their motility and invasiveness in vitro and cancer metastasis in vivo. In contrast, knockdown of PPM1B in MCF-7 and MDA-MB-468 human breast cancer cells that express endogenous PPM1B enhances EGF-induced RhoGDI1 phosphorylation, activation of Rho GTPases, and cancer cell migration and invasion. Knockdown of RhoA or Rac1 by siRNA reverses the enhanced cell migration seen after PP1MB depletion. Collectively, these results indicate that PPM1B negatively regulates cancer cell motility and invasiveness through dephosphorylating RhoGDI1.
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http://dx.doi.org/10.1016/j.canlet.2018.01.002DOI Listing
March 2018

Overexpression of Neuron-Specific Enolase as a Prognostic Factor in Patients with Gastric Cancer.

J Gastric Cancer 2017 Sep 25;17(3):228-236. Epub 2017 Aug 25.

Gyeongnam Regional Cancer Center, Gyeongsang National University School of Medicine, Jinju, Korea.

Purpose: Enolase is a cytoplasmic enzyme that catalyzes the conversion of 2-phosphoglycerate to phosphoenolpyruvate in the glycolytic pathway. The aim of this study was to investigate whether the overexpression of neuron-specific enolase (NSE) can serve as a prognostic factor in patients with gastric cancer (GC).

Materials And Methods: To assess its prognostic value in GC, NSE expression was measured by immunohistochemistry in a clinically annotated tissue microarray comprising of 327 human GC specimens. Cytoplasmic NSE expression was scored from 0 to 4, reflecting the percentage of NSE-positive cells.

Results: In terms of histology as per the World Health Organization criteria (P=0.340), there were no differences between the NSE overexpression (NSE-OE) and NSE underexpression (NSE-UE) groups. The NSE-OE group showed a significantly lower rate of advanced GC (P<0.010), lymph node metastasis (P=0.010), advanced stage group (P<0.010), cancer-related death (P<0.010), and cancer recurrence (P<0.010). Additionally, a Kaplan-Meier survival analysis revealed that the NSE-OE group had longer cumulative survival times than the NSE-UE group (log-rank test, P<0.010). However, there were no significant differences in the serum levels of NSE expression in patients with GC and healthy volunteers (P=0.280).

Conclusions: Patients with NSE overexpressing GC tissues showed better prognostic results, implying that NSE could be a candidate biomarker of GC.
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http://dx.doi.org/10.5230/jgc.2017.17.e28DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5620092PMC
September 2017

Extracellular cystatin SN and cathepsin B prevent cellular senescence by inhibiting abnormal glycogen accumulation.

Cell Death Dis 2017 04 6;8(4):e2729. Epub 2017 Apr 6.

Division of Applied Life Science (BK21 Plus), Gyeongsang National University, Jinju, Republic of Korea.

Cystatin SN (CST1), a known inhibitor of cathepsin B (CatB), has important roles in tumor development. Paradoxically, CatB is a member of the cysteine cathepsin family that acts in cellular processes, such as tumor development and invasion. However, the relationship between CST1 and CatB, and their roles in tumor development are poorly understood. In this study, we observed that the knockdown of CST1 induced the activity of senescence-associated β-galactosidase, a marker of cellular senescence, and expression of senescence-associated secretory phenotype genes, including interleukin-6 and chemokine (C-C motif) ligand 20, in MDA-MB-231 and SW480 cancer cells. Furthermore, CST1 knockdown decreased extracellular CatB activity, and direct CatB inhibition, using specific inhibitors or shCatB, induced cellular senescence. Reconstitution of CST1 restored CatB activity and inhibited cellular senescence in CST1 knockdown cells. CST1 knockdown or CatB inhibition increased glycogen synthase (GS) kinase 3β phosphorylation at serine 9, resulting in the activation of GS and the induction of glycogen accumulation associated with cellular senescence. Importantly, CST1 knockdown suppressed cancer cell proliferation, soft agar colony growth and tumor growth in a xenograft model. These results indicate that CST1-mediated extracellular CatB activity enhances tumor development by preventing cellular senescence. Our findings suggest that antagonists of CST1 or inhibitors of CatB are potential anticancer agents.
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http://dx.doi.org/10.1038/cddis.2017.153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5477579PMC
April 2017

Cytotoxic effects of kazinol A derived from Broussonetia papyrifera on human bladder cancer cells, T24 and T24R2.

Phytomedicine 2016 Nov 24;23(12):1462-1468. Epub 2016 Aug 24.

Division of Applied Life Science (BK21 Plus), Gyeongsang National University, Jinju, Republic of Korea; PMBBRC, Gyeongsang National University, Jinju, Republic of Korea. Electronic address:

Background: Broussonetia papyrifera (B. papyrifera), also known as paper mulberry, has been used as a traditional medicine for the treatment of several diseases, including ophthalmic disorders and impotency. However, the biological activity of kazinol A (1) among flavonols isolated from B. papyrifera has not been identified.

Purpose: We identified a candidate metabolite for anti-human bladder cancer treatment from B. papyrifera and investigated the possible molecular mechanisms underlying its cytotoxic effects in T24 and cisplatin-resistant T24R2 human bladder cancer cells.

Methods: T24 and T24R2 cells were treated with five flavonols from B. papyrifera and their cytotoxic effects were determined using MTT assay, cell cycle analysis, mitochondrial membrane potential, and propidium iodide staining. Autophagy rate was calculated by counting LC3-GFP dots in the cells. All related protein expressions were analyzed by immunoblotting.

Results: Compound 1 showed relatively higher cytotoxicity in the human bladder cancer cells, T24 and T24R2, rather than other tissues-originated cancer cells. Compound 1 significantly attenuated cell growth through G arrest mediated by a decrease in cyclin D1 and an increase of p21. Apoptosis and autophagy induced by compound 1 treatment was accompanied by a modulation of the AKT-BAD pathway and AMPK-mTOR pathway, respectively.

Conclusions: Our results suggest that compound 1 induces cytotoxic effects in human bladder cancer cells, including the cisplatin-resistant T24R2. Compound 1 may be a candidate for the development of effective anti-cancer drug on human urinary bladder cancer.
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http://dx.doi.org/10.1016/j.phymed.2016.08.005DOI Listing
November 2016

Depigmentation of α-melanocyte-stimulating hormone-treated melanoma cells by β-mangostin is mediated by selective autophagy.

Exp Dermatol 2017 07 16;26(7):585-591. Epub 2016 Nov 16.

Division of Applied Life Science (BK21 Plus), Gyeongsang National University, Jinju, Korea.

Melanogenesis is a key pathway for the regulation of skin pigmentation and the development of skin-lightening/skin-whitening drugs or cosmetics. In this study, we found that β-mangostin from seedcases of Garcinia mangostana inhibited α-melanocyte-stimulating hormone (α-MSH)-mediated melanogenesis in B16F10 melanoma cells and a three-dimensional human skin model. β-Mangostin significantly inhibited the protein level of tyrosinase induced by α-MSH in UPS (ubiquitin proteasome system)-independent and lysosome-dependent manner. The inhibition of autophagy by 3-methyladenine treatment or ATG5 knockdown effectively recovered premelanosome protein as well as tyrosinase degraded by the β-mangostin treatment. However, rapamycin, a representative non-selective autophagy inducer, triggered autophagy in α-MSH-stimulated cells, which was characterized by a considerable decrease in p62, but it was unable to inhibit melanogenesis. Melanosome-engulfing autophagosomes were observed using transmission electron microscopy. Furthermore, previously formed melanin could be degraded effectively in an autophagy-dependent manner in β-mangostin-treated cells. Taken together, our results suggest that β-mangostin inhibits the melanogenesis induced by α-MSH via an autophagy-dependent mechanism, and thus, the depigmentation effect of β-mangostin may depend on autophagy targeted at the melanosome rather than non-selective autophagy.
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http://dx.doi.org/10.1111/exd.13233DOI Listing
July 2017

Suppression of 14-3-3γ-mediated surface expression of ANO1 inhibits cancer progression of glioblastoma cells.

Sci Rep 2016 05 23;6:26413. Epub 2016 May 23.

School of Biosystem and Biomedical Science, College of Health Science, Korea University, Seoul 02841, Republic of Korea.

Anoctamin-1 (ANO1) acts as a Ca(2+)-activated Cl(-) channel in various normal tissues, and its expression is increased in several different types of cancer. Therefore, understanding the regulation of ANO1 surface expression is important for determining its physiological and pathophysiological functions. However, the trafficking mechanism of ANO1 remains elusive. Here, we report that segment a (N-terminal 116 amino acids) of ANO1 is crucial for its surface expression, and we identified 14-3-3γ as a binding partner for anterograde trafficking using yeast two-hybrid screening. The surface expression of ANO1 was enhanced by 14-3-3γ, and the Thr9 residue of ANO1 was critical for its interaction with 14-3-3γ. Gene silencing of 14-3-3γ and/or ANO1 demonstrated that suppression of ANO1 surface expression inhibited migration and invasion of glioblastoma cells. These findings provide novel therapeutic implications for glioblastomas, which are associated with poor prognosis.
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http://dx.doi.org/10.1038/srep26413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4876403PMC
May 2016

RhoGDI2 promotes epithelial-mesenchymal transition via induction of Snail in gastric cancer cells.

Oncotarget 2014 Mar;5(6):1554-64

Division of Applied Life Science (BK21 plus), Research Institute of Life Sciences, Gyeongsang National University, Jinju, Korea.

Rho GDP dissociation inhibitor 2 (RhoGDI2) expression correlates with tumor growth, metastasis, and chemoresistance in gastric cancer. Here, we show that RhoGDI2 functions in the epithelial-mesenchymal transition (EMT), which is responsible for invasiveness during tumor progression. This tumorigenic activity is associated with repression of E-cadherin by RhoGDI2 via upregulation of Snail. Overexpression of RhoGDI2 induced phenotypic changes consistent with EMT in gastric cancer cells, including abnormal epithelial cell morphology, fibroblast-like properties, and reduced intercellular adhesion. RhoGDI2 overexpression also resulted in decreased expression of the epithelial markers E-cadherin and β-catenin and increased expression of the mesenchymal markers vimentin and fibronectin. Importantly, RhoGDI2 overexpression also stimulated the expression of Snail, a repressor of E-cadherin and inducer of EMT, but not other family members such as Slug or Twist. RNA interference-mediated knockdown of Snail expression suppressed RhoGDI2-induced EMT and invasion, confirming that the effect was Snail-specific. These results indicate that RhoGDI2 plays a critical role in tumor progression in gastric cancer through induction of EMT. Targeting RhoGDI2 may thus be a useful strategy to inhibit gastric cancer cell invasion and metastasis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4039231PMC
http://dx.doi.org/10.18632/oncotarget.1733DOI Listing
March 2014

VEGF-C mediates RhoGDI2-induced gastric cancer cell metastasis and cisplatin resistance.

Int J Cancer 2014 Oct 4;135(7):1553-63. Epub 2014 Mar 4.

Rho GDP dissociation inhibitor 2 (RhoGDI2) expression is correlated with tumor growth, metastasis and chemoresistance in gastric cancer. However, the mechanisms by which RhoGDI2 promotes tumor cell survival and metastasis remain unclear. In this study, we clearly demonstrate that RhoGDI2 upregulates VEGF-C expression and RhoGDI2 expression is positively correlated with VEGF-C expression in human gastric tumor tissues as well as parental gastric cancer cell lines. VEGF-C depletion suppressed RhoGDI2-induced gastric cancer metastasis and sensitized RhoGDI2-overexpressing cells to cisplatin-induced apoptosis in vitro and in vivo. Secreted VEGF-C enhanced gastric cancer cell invasion and conferred cisplatin resistance to RhoGDI2-overexpressing cells. We also show that RhoGDI2 positively regulates Rac1 activity in gastric cancer cells. Inhibition of Rac1 expression suppressed RhoGDI2-induced VEGF-C expression, and this inhibition was associated with decreased invasiveness and increased sensitivity to cisplatin in RhoGDI2-overexpressing cells. Our results indicate that RhoGDI2 might be a potential therapeutic target for simultaneously reducing metastasis risk and enhancing chemotherapy efficacy in gastric cancer.
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http://dx.doi.org/10.1002/ijc.28801DOI Listing
October 2014

OCT-1 overexpression is associated with poor prognosis in patients with well-differentiated gastric cancer.

Tumour Biol 2014 Jun 25;35(6):5501-9. Epub 2014 Feb 25.

Department of Surgery/Gyeongnam Regional Cancer Center, College of Natural Sciences, Gyeongsang National University, 79 Gangnam-ro, Jinju, Gyeongsang South Province, 660-702, South Korea.

Octamer transcription factor-1 (OCT-1) is a well-known transcription factor that is reportedly overexpressed in intestinal metaplasia and gastric carcinoma in the intestine. In this study, we investigated OCT-1 overexpression as a prognostic factor for gastric cancer. The association between OCT-1 overexpression (detected using immunohistochemistry) and clinicopathological features including survival was evaluated. In vitro gain-of-function approaches were utilized to assess the function of OCT-1 in malignancy. Analysis of OCT-1 expression in patients with gastric cancer with well-differentiated carcinoma as per the World Health Organization classification showed that OCT-1 overexpression was correlated with advanced tumor invasion (58.8 % of patients with advanced tumor invasion vs. 21.2 % of patients with early tumor invasion; p<0.01), lymph node metastasis (63.9 % of patients with metastasis vs. 24.1 % of those without; p=0.015), and cancer recurrence (83.3 % of patients with recurrence vs. 25.4 % of those without; p<0.01), as well as a lower survival rate (62.8 vs. 87.9 Mo; p<0.01). However, there were no significant differences in the levels of OCT-1 expression in gastric cancer patients with other carcinoma types (p>0.05). Furthermore, we found that the proliferation rate of OCT-1-overexpressing MKN-45 cells was higher than that of the control cells. OCT-1 overexpression may be a marker for poor prognosis in patients with well-differentiated gastric adenocarcinoma.
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http://dx.doi.org/10.1007/s13277-014-1724-4DOI Listing
June 2014

14-3-3σ attenuates RhoGDI2-induced cisplatin resistance through activation of Erk and p38 in gastric cancer cells.

Oncotarget 2013 Nov;4(11):2045-56

Division of Applied Life Science/Research Institute of Life Science, Graduate School of Gyeongsang National University, Jinju, Korea.

Rho GDP dissociation inhibitor 2 (RhoGDI2) promotes tumor growth and malignant progression and enhances chemoresistance of gastric cancer. Recently, we noted an inverse correlation between RhoGDI2 and 14-3-3σ expression, which suggests that 14-3-3σ is a target of gastric cancer metastasis and the chemoresistance-promoting effect of RhoGDI2. Herein, we evaluated whether 14-3-3σ is regulated by RhoGDI2 and is functionally important for the RhoGDI2-induced cisplatin resistance of gastric cancer cells. We used highly metastatic and cisplatin-resistant RhoGDI2-overexpressing SNU-484 cells and observed decreased 14-3-3σ mRNA and protein expression. Depletion of 14-3-3σ in SNU-484 control cells enhanced cisplatin resistance, whereas restoration of 14-3-3σ in RhoGDI2-overexpressing SNU-484 cells impaired cisplatin resistance in vitro and in vivo. We also found that the phosphorylation levels of Erk and p38 kinases significantly decreased in RhoGDI2-overexpressing SNU-484 cells and recovered after 14-3-3σ expression, and that decreased activities of these kinases were critical for RhoGDI2-induced cisplatin resistance. In conclusion, 14-3-3σ is a RhoGDI2-regulated gene that appears to be important for suppressing the chemoresistance of gastric cancer cells.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3875768PMC
http://dx.doi.org/10.18632/oncotarget.1334DOI Listing
November 2013

Prognostic value of CAPZA1 overexpression in gastric cancer.

Int J Oncol 2013 May 27;42(5):1569-77. Epub 2013 Mar 27.

Department of Surgery, Postgraduate School of Medicine, Gyeongnam Regional Cancer Center, Gyeongsang National University, Jinju, Republic of Korea.

F-actin capping protein α1 subunit (CAPZA1) was previously identified in a proteomic analysis of human gastric cancer clinical specimens and selected for further study. The association between CAPZA1 overexpression, detected by immunohistochemistry, and clinicopathological features including survival were evaluated. In vitro gain-of-function and loss-of-function approaches were utilized to assess the function of CPAZA1 in malignancy. Univariate analysis revealed that poorly differentiated disease, according to the World Health Organization (WHO) classification, advanced T stage, positive lymph nodes, high TNM stage, D2 lymph node dissection, adjuvant chemotherapy and CAPZA1 underexpression were significantly associated with cancer-related death (p<0.05); however, only high TNM stage remained significantly associated by multivariate analysis (p<0.01). CAPZA1 overexpression was associated with well differentiated histology, smaller tumor size, lower T stage, absence of lymph node metastasis, lower TNM stage, lower recurrence rate and longer survival time, compared to CAPZA1 underexpression. In vitro, forced expression of CAPZA1 caused a significant decrease in gastric cancer cell migration and invasion, whereas CAPZA1 depletion had the opposite effect. The present study suggests that CAPZA1 could be a marker of good prognosis in gastric cancer and shows that CAPZA1 is associated with decreased cancer cell migration and invasion.
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http://dx.doi.org/10.3892/ijo.2013.1867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3661194PMC
May 2013

Pyrophosphatase overexpression is associated with cell migration, invasion, and poor prognosis in gastric cancer.

Tumour Biol 2012 Dec 14;33(6):1889-98. Epub 2012 Jul 14.

Department of Surgery/Gyeongnam Regional Cancer Center, Gyeongsang National University, Jinju, South Korea.

Inorganic pyrophosphatase (PPase) catalyzes the hydrolysis of pyrophosphate to form orthophosphate. Pyrophosphate can substitute for ATP under certain circumstances. We previously conducted a proteomic analysis to investigate tumor-specific protein expression in gastric cancer, and PPase was identified as a potential gastric tumor-specific marker; it was therefore selected for further study. Clinicopathological analysis, using proteomic analysis and immunohistochemistry, was used to validate PPase as a prognostic marker in gastric cancers. Proteomic analysis showed that PPase was overexpressed in patients with lymph node (LN) metastases and high tumor node metastasis (TNM) stages (p < 0.05). Based on immunohistochemistry, patients whose tumors overexpressed PPase had higher T stages, LN metastasis, a higher TNM stage, a higher cancer recurrence rate, and shorter survival times than patients whose tumors exhibited PPase underexpression (p < 0.05). Gain-of-function and loss-of-function approaches were employed to examine the malignant phenotypes of PPase-overexpressing or PPase-depleted cells. A decrease in PPase expression caused a significant decrease in gastric cancer cell migration and invasion in vitro, whereas forced overexpression of PPase enhanced migration but not invasion. Our findings indicate that PPase is involved in gastric tumor progression and that PPase may be a useful marker for poor prognosis of human gastric cancers.
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http://dx.doi.org/10.1007/s13277-012-0449-5DOI Listing
December 2012

Proteomics-based strategy to delineate the molecular mechanisms of RhoGDI2-induced metastasis and drug resistance in gastric cancer.

J Proteome Res 2012 Apr 12;11(4):2355-64. Epub 2012 Mar 12.

Department of Microbiology/Research Institute of Life Science, College of Natural Sciences, Gyeongsang National University, Jinju, Korea.

Rho GDP dissociation inhibitor 2 (RhoGDI2) was initially identified as a regulator of the Rho family of GTPases. Our recent works suggest that RhoGDI2 promotes tumor growth and malignant progression, as well as enhances chemoresistance in gastric cancer. Here, we delineate the mechanism by which RhoGDI2 promotes gastric cancer cell invasion and chemoresistance using two-dimensional gel electrophoresis (2-DE) on proteins derived from a RhoGDI2-overexpressing SNU-484 human gastric cancer cell line and control cells. Differentially expressed proteins were identified using matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF-MS). In total, 47 differential protein spots were identified; 33 were upregulated, and 14 were downregulated by RhoGDI2 overexpression. Upregulation of SAE1, Cathepsin D, Cofilin1, CIAPIN1, and PAK2 proteins was validated by Western blot analysis. Loss-of-function analysis using small interference RNA (siRNA) directed against candidate genes reveals the need for CIAPIN1 and PAK2 in RhoGDI2-induced cancer cell invasion and Cathepsin D and PAK2 in RhoGDI2-mediated chemoresistance in gastric cancer cells. These data extend our understanding of the genes that act downstream of RhoGDI2 during the progression of gastric cancer and the acquisition of chemoresistance.
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http://dx.doi.org/10.1021/pr2011186DOI Listing
April 2012

PLCγ is required for RhoGDI2-mediated cisplatin resistance in gastric cancer.

Biochem Biophys Res Commun 2011 Oct 1;414(3):575-80. Epub 2011 Oct 1.

Department of Microbiology/Research Institute of Life Science, College of Natural Sciences, Gyeongsang National University, Jinju 660-701, Republic of Korea.

Rho GDP dissociation inhibitor 2 (RhoGDI2) is a regulator of the Rho family GTPases. Recent work from our laboratory suggests that RhoGDI2 expression potentially enhances resistance to cisplatin as well as promotes tumor growth and malignant progression in gastric cancer. In this study, we demonstrate that phospholipase C-gamma (PLCγ) is required for RhoGDI2-mediated cisplatin resistance and cancer cell invasion in gastric cancer. The levels of phosphorylated PLCγ are markedly enhanced in RhoGDI2-overexpressing SNU-484 cells and, by contrast, repressed in RhoGDI2-depleted MKN-28 cells. Depletion of PLCγ expression or inhibition of its activity not only significantly increases cisplatin-induced apoptosis but also suppresses the invasive ability of RhoGDI2-overexpressing SNU-484 cells. Taken together, our results suggest that PLCγ plays a key role in RhoGDI2-mediated cisplatin resistance and cell invasion in gastric cancer cells.
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http://dx.doi.org/10.1016/j.bbrc.2011.09.121DOI Listing
October 2011

RhoGDI2 confers gastric cancer cells resistance against cisplatin-induced apoptosis by upregulation of Bcl-2 expression.

Cancer Lett 2011 Dec 24;311(1):48-56. Epub 2011 Jun 24.

Department of Microbiology/Research Institute of Life Science, College of Natural Sciences, Gyeongsang National University, Jinju, Republic of Korea.

Rho GDP dissociation inhibitor (RhoGDI)2 has been identified as a regulator of Rho family GTPase. Recently, we suggested that RhoGDI2 could promote tumor growth and malignant progression in gastric cancer. In this study, we demonstrate that RhoGDI2 contributes to another important feature of aggressive cancers, i.e., resistance to chemotherapeutic agents such as cisplatin. Forced expression of RhoGDI2 attenuated cisplatin-induced apoptosis, whereas RhoGDI2 depletion showed opposite effects in vitro. Moreover, the increased anti-apoptotic effect of RhoGDI2 on cisplatin was further validated in RhoGDI2-overexpressing SNU-484 xenograft model in nude mice. Furthermore, we identified Bcl-2 as a major determinant of RhoGDI2-mediated cisplatin resistance in gastric cancer cells. Depletion of Bcl-2 expression significantly increased cisplatin-induced apoptosis in RhoGDI2-overexpressing gastric cancer cells, whereas overexpression of Bcl-2 blocked cisplatin-induced apoptosis in RhoGDI2-depleted gastric cancer cells. Overall, these findings establish RhoGDI2 as an important therapeutic target for simultaneously enhancing chemotherapy efficacy and reducing metastasis risk in gastric cancer.
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http://dx.doi.org/10.1016/j.canlet.2011.06.024DOI Listing
December 2011

Gadd45b mediates Fas-induced apoptosis by enhancing the interaction between p38 and retinoblastoma tumor suppressor.

J Biol Chem 2010 Aug 17;285(33):25500-5. Epub 2010 Jun 17.

Department of Microbiology/Research Institute of Life Science, College of Natural Sciences, Gyeongsang National University, Jinju 660-701, Korea.

Gadd45b has been known as a positive mediator of apoptosis induced by certain cytokines and oncogenes. Here, we identified Gadd45b as an effector of Fas-induced apoptosis and found that p38-mediated Rb hyperphosphorylation is one of the mechanisms of Fas-induced apoptosis in murine hepatocyte AML12 cells. Gadd45b has been shown to activate p38 through its physical interaction with MTK1 and induce apoptosis. However, in this study, we have showed that the function of Gadd45b during Fas-induced apoptosis in AML12 cells is different from that reported in previous studies. Depletion of Gadd45b expression did not inhibit the phosphorylation of p38, but it suppressed p38-mediated Rb phosphorylation and apoptosis in response to Fas stimulation by reducing the interaction between p38 and Rb. Ectopic expression of Gadd45b was sufficient to enhance this interaction. These findings suggest that Gadd45b mediates p38-induced Rb phosphorylation by enhancing the interaction between p38 and Rb during Fas-induced apoptosis in murine hepatocytes.
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http://dx.doi.org/10.1074/jbc.M109.091413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2919113PMC
August 2010