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Article ; Online: Correction: Targeting TMEM205 mediated drug resistance in ovarian clear cell carcinoma using oncolytic virus.

Saini, Uksha / Smith, Brentley Q / Dorayappan, Kalpana Deepa Priya / Yoo, Ji Young / Maxwell, G Larry / Kaur, Balveen / Konishi, Ikuo / O'Malley, David / Cohn, David E / Selvendiran, Karuppaiyah

Journal of ovarian research

2023 Volume 16, Issue 1, Page(s) 38

Language	English
Publishing date	2023-02-13
Publishing country	England
Document type	Published Erratum
ZDB-ID	2455679-8
ISSN	1757-2215 ; 1757-2215
ISSN (online)	1757-2215
ISSN	1757-2215
DOI	10.1186/s13048-023-01111-7
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Article ; Online: Targeting TMEM205 mediated drug resistance in ovarian clear cell carcinoma using oncolytic virus.

Saini, Uksha / Smith, Brentley Q / Dorayappan, Kalpana Deepa Priya / Yoo, Ji Young / Maxwell, G Larry / Kaur, Balveen / Konishi, Ikuo / O'Malley, David / Cohn, David E / Selvendiran, Karuppaiyah

Journal of ovarian research

2022 Volume 15, Issue 1, Page(s) 130

Abstract: Background: Ovarian clear cell carcinoma (OCCC) accounts for approximately 8-10% of epithelial ovarian cancers in the United States. Although it is rare, OCCC usually presents with treatment challenges and the overall prognosis is far worse than high ... ...

Abstract	Background: Ovarian clear cell carcinoma (OCCC) accounts for approximately 8-10% of epithelial ovarian cancers in the United States. Although it is rare, OCCC usually presents with treatment challenges and the overall prognosis is far worse than high grade serous ovarian cancer HGSOC. The objective of this study was to examine the therapeutic relevance of combining oncolytic virus with cisplatin for ovarian cancer clear cell carcinoma (OCCC). Results: We identified that TMEM205, a recently discovered transmembrane protein, contributes to chemoresistance in OCCC cells via the exosomal pathway. Mechanistically, TMEM205 undergoes ligand-independent constitutive endocytosis and co-localizes with Rab11 to contribute to the late recycling endosomes in a clathrin-independent manner. Further, we observed that oncolytic virus (oHSV) pretreatment followed by treatment with cisplatin decreases TMEM205 expression and sensitizes cells to cisplatin in a synergistic manner in OCCC cells. TMEM205 interacts with glycoprotein-C of oHSV post-infection; both of these proteins undergo ubiquitination and ultimately get shuttled outside the cell via exosomes. Thus, we demonstrate the mechanotransduction pathway of TMEM205-mediated chemoresistance along with targeting this pathway using oHSV and cisplatin as a powerful therapeutic strategy for OCCC. oHSV combination with cisplatin inhibits OCCC tumor growth in vivo in immunodeficient and immunocompetent mice models. Conclusion: Our results suggest that the combination of oHSV and cisplatin in immunocompetent as well as immune deficient OCCC tumor bearing mice reduces overall tumor burden as well as metastatic disease thereby providing survival benefit. Additionally, the detection of TMEM205 in exosomal cargo early in OCCC development has potential to be exploited as a biomarker.
MeSH term(s)	Animals ; Mice ; Humans ; Female ; Oncolytic Viruses/genetics ; Mechanotransduction, Cellular ; Ovarian Neoplasms/drug therapy ; Ovarian Neoplasms/genetics ; Drug Resistance ; Carcinoma ; Membrane Proteins/genetics
Chemical Substances	TMEM205 protein, human ; Membrane Proteins
Language	English
Publishing date	2022-12-07
Publishing country	England
Document type	Journal Article
ZDB-ID	2455679-8
ISSN	1757-2215 ; 1757-2215
ISSN (online)	1757-2215
ISSN	1757-2215
DOI	10.1186/s13048-022-01054-5
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Article ; Online: Aberrant expression of TMEM205 signaling promotes platinum resistance in ovarian cancer: An implication for the antitumor potential of DAP compound.

Calo, Corinne A / Smith, Brentley Q / Dorayappan, Kalpana Deepa Priya / Saini, Uksha / Lightfoot, Michelle / Wagner, Vincent / Kalaiyarasan, Deepika / Cosgrove, Casey / Wang, Qi-En / Maxwell, G Larry / Kálai, Tamás / Kuppusamy, Periannan / Cohn, David E / Selvendiran, Karuppaiyah

Gynecologic oncology

2021 Volume 164, Issue 1, Page(s) 136–145

Abstract: Introduction: TMEM205 is a novel transmembrane protein associated with platinum resistance (PR) in epithelial ovarian carcinoma (OC), however, the specific mechanisms associated with this resistance remain to be elucidated.: Methods: TMEM205 ... ...

Abstract	Introduction: TMEM205 is a novel transmembrane protein associated with platinum resistance (PR) in epithelial ovarian carcinoma (OC), however, the specific mechanisms associated with this resistance remain to be elucidated. Methods: TMEM205 expression was evaluated in platinum-sensitive (PS) versus platinum resistant (PR) ovarian cancer cell lines and patient serum/tissues. Exosomal efflux of platinum was evaluated with inductively coupled plasma mass spectrometry (ICP-MS) after pre-treatment with small molecule inhibitors (L-2663/L-2797) of TMEM205 prior to treatment with platinum. Cytotoxicity of combination treatment was confirmed in vitro and in an in vivo model. Results: TMEM205 expression was 10-20 fold higher in PR compared to PS ovarian cancer cell lines, serum samples, and tissues. Co-localization with CD1B was confirmed by in-situ proximity ligation assay suggesting that TMEM205 may mediate PR via the exosomal pathway. Exosomal secretion was significantly increased 5-10 fold in PR cell lines after treatment with carboplatin compared to PS cell lines. Pre-treatment with L-2663 prior to carboplatin resulted in significantly increased intracellular concentration of fluorescently-labeled cisplatin and decreased exosomal efflux of platinum. Decreased cell survival and tumor growth in vitro and in vivo was observed when PR cells were treated with a combination of L-2663 with carboplatin compared to carboplatin alone. Conclusion: TMEM205 appears to be involved in the development of PR in ovarian cancer through the exosomal efflux of platinum agents. This study provides pre-clinical evidence that TMEM205 could serve as a possible biomarker for PR as well as a therapeutic target in combination with platinum agents.
MeSH term(s)	Animals ; Female ; Humans ; Mice ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Carboplatin/pharmacology ; Carboplatin/therapeutic use ; Cell Line, Tumor/drug effects ; Cell Line, Tumor/metabolism ; Disease Models, Animal ; Drug Resistance, Neoplasm/drug effects ; Membrane Proteins/antagonists & inhibitors ; Membrane Proteins/drug effects ; Membrane Proteins/metabolism ; Mice, Nude ; Ovarian Neoplasms/drug therapy ; Ovarian Neoplasms/metabolism
Chemical Substances	Antineoplastic Agents ; Carboplatin (BG3F62OND5) ; Membrane Proteins ; TMEM205 protein, human ; L-2663
Language	English
Publishing date	2021-10-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	801461-9
ISSN	1095-6859 ; 0090-8258
ISSN (online)	1095-6859
ISSN	0090-8258
DOI	10.1016/j.ygyno.2021.10.076
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Zs.A 885: Show issues

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Article ; Online: Eliciting an immune-mediated antitumor response through oncolytic herpes simplex virus-based shared antigen expression in tumors resistant to viroimmunotherapy.

Ghonime, Mohammed G / Saini, Uksha / Kelly, Michael C / Roth, Justin C / Wang, Pin-Yi / Chen, Chun-Yu / Miller, Katherine / Hernandez-Aguirre, Ilse / Kim, Yeaseul / Mo, Xiaokui / Stanek, Joseph R / Cripe, Tim / Mardis, Elaine / Cassady, Kevin A

Journal for immunotherapy of cancer

2021 Volume 9, Issue 10

Abstract: Background: Oncolytic virotherapy (OV) is an immunotherapy that incorporates viral cancer cell lysis with engagement of the recruited immune response against cancer cells. Pediatric solid tumors are challenging targets because they contain both an inert ...

Abstract	Background: Oncolytic virotherapy (OV) is an immunotherapy that incorporates viral cancer cell lysis with engagement of the recruited immune response against cancer cells. Pediatric solid tumors are challenging targets because they contain both an inert immune environment and a quiet antigenic landscape, making them more resistant to conventional OV approaches. Further complicating this, herpes simplex virus suppresses host gene expression during virotherapy infection. Methods: We therefore developed a multimodal oncolytic herpes simplex virus (oHSV) that expresses ephrin A2 (EphA2), a shared tumor-associated antigen (TAA) expressed by many tumors to improve immune-mediated antitumor activity. We verified the virus genotypically and phenotypically and then tested it in an oHSV-resistant orthotopic model (including immunophenotypic analysis), in flank and in T cell-deficient mouse models. We then assessed the antigen-expressing virus in an unrelated peripheral tumor model that also expresses the shared tumor antigen and evaluated functional T-cell response from the treated mice. Results: Virus-based EphA2 expression induces a robust acquired antitumor immune responses in both an oHSV-resistant murine brain and peripheral tumor model. Our new multimodal oncolytic virus (1) improves survival in viroimmunotherapy resistant tumors, (2) alters both the infiltrating and peripheral T-cell populations capable of suppressing tumor growth on rechallenge, and (3) produces EphA2-specific CD8 effector-like populations. Conclusions: Our results suggest that this flexible viral-based platform enables immune recognition of the shared TAA and improves the immune-therapeutic response, thus making it well suited for low-mutational load tumors.
MeSH term(s)	Animals ; Disease Models, Animal ; Herpes Simplex/metabolism ; Immunotherapy/methods ; Mice ; Neoplasms/drug therapy ; Neoplasms/virology ; Oncolytic Virotherapy/methods ; Oncolytic Viruses/metabolism
Language	English
Publishing date	2021-09-29
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2719863-7
ISSN	2051-1426 ; 2051-1426
ISSN (online)	2051-1426
ISSN	2051-1426
DOI	10.1136/jitc-2021-002939
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Article ; Online: Oncolytic HSV Therapy Modulates Vesicular Trafficking Inducing Cisplatin Sensitivity and Antitumor Immunity.

Hong, Bangxing / Chapa, Valerie / Saini, Uksha / Modgil, Puneet / Cohn, David E / He, Guangan / Siddik, Zahid H / Sood, Anil K / Yan, Yuanqing / Selvendiran, Karuppaiyah / Pei, Guangsheng / Zhao, Zhongming / Yoo, Ji Young / Kaur, Balveen

Clinical cancer research : an official journal of the American Association for Cancer Research

2020 Volume 27, Issue 2, Page(s) 542–553

Abstract: Purpose: Here we investigated the impact of oncolytic herpes simplex virus (HSV) treatment on cisplatin sensitivity of platinum-resistant ovarian cancer, and the impact of the combination on immunotherapy.: Experimental design: Therapeutic efficacy ... ...

Abstract	Purpose: Here we investigated the impact of oncolytic herpes simplex virus (HSV) treatment on cisplatin sensitivity of platinum-resistant ovarian cancer, and the impact of the combination on immunotherapy. Experimental design: Therapeutic efficacy of the combination was assessed in platinum-resistant human and murine ovarian cancer peritoneal metastatic mouse models ( Results: Gene Ontology pathway analysis uncovered disruption of cellular extracellular vesicle (EV)-related pathways in infected cells (FDR = 2.97E-57). Mechanistically, we identified reduced expression of transporters expressed on EV implicated in cisplatin efflux. The increased cisplatin retention led to increased cisplatin-DNA adducts, which resulted in micronuclei and the subsequent activation of cGAS-STING pathway with a significant activation of innate immune cells and translated to an increase in antitumor immunity and efficacy. In mice bearing platinum-resistant ovarian cancer, we also observed a feedback induction of PD-L1 on tumor cells, which sensitized combination-treated mice to anti-PD-1 immune checkpoint therapy. Conclusions: To our knowledge, this is the first report to show HSV-induced cisplatin retention in infected cells. The consequential increased damaged DNA was then expelled from cells as micronuclei which resulted in induction of inflammatory responses and education of antitumor immunity. The combination therapy also created an environment that sensitized tumors to immune checkpoint therapy.
MeSH term(s)	Animals ; Antineoplastic Agents/therapeutic use ; Cell Line, Tumor ; Cells, Cultured ; Cisplatin/therapeutic use ; Combined Modality Therapy ; DNA Adducts/genetics ; DNA Adducts/immunology ; Disease Models, Animal ; Female ; Herpesvirus 1, Human/physiology ; Humans ; Immunotherapy/methods ; Mice, Inbred C57BL ; Mice, Inbred NOD ; Mice, Knockout ; Mice, SCID ; Oncolytic Virotherapy/methods ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/therapy ; Ovarian Neoplasms/virology ; Signal Transduction/genetics ; Signal Transduction/immunology ; Treatment Outcome ; Xenograft Model Antitumor Assays/methods ; Mice
Chemical Substances	Antineoplastic Agents ; DNA Adducts ; Cisplatin (Q20Q21Q62J)
Language	English
Publishing date	2020-10-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-20-2210
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Zs.A 4223: Show issues

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ab Jg. 2022: Lesesaal (EG)

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Article ; Online: Hypoxia-induced exosomes contribute to a more aggressive and chemoresistant ovarian cancer phenotype: a novel mechanism linking STAT3/Rab proteins.

Dorayappan, Kalpana Deepa Priya / Wanner, Ross / Wallbillich, John J / Saini, Uksha / Zingarelli, Roman / Suarez, Adrian A / Cohn, David E / Selvendiran, Karuppaiyah

Oncogene

2018 Volume 37, Issue 28, Page(s) 3806–3821

Abstract: Hypoxia-mediated tumor progression, metastasis, and drug resistance are major clinical challenges in ovarian cancer. Exosomes released in the hypoxic tumor microenvironment may contribute to these challenges by transferring signaling proteins between ... ...

Abstract	Hypoxia-mediated tumor progression, metastasis, and drug resistance are major clinical challenges in ovarian cancer. Exosomes released in the hypoxic tumor microenvironment may contribute to these challenges by transferring signaling proteins between cancer cells and normal cells. We observed that ovarian cancer cells exposed to hypoxia significantly increased their exosome release by upregulating Rab27a, downregulating Rab7, LAMP1/2, NEU-1, and also by promoting a more secretory lysosomal phenotype. STAT3 knockdown in ovarian cancer cells reduced exosome release by altering the Rab family proteins Rab7 and Rab27a under hypoxic conditions. We also found that exosomes from patient-derived ascites ovarian cancer cell lines cultured under hypoxic conditions carried more potent oncogenic proteins-STAT3 and FAS that are capable of significantly increasing cell migration/invasion and chemo-resistance in vitro and tumor progression/metastasis in vivo. Hypoxic ovarian cancer cells derived exosomes (HEx) are proficient in re-programming the immortalized fallopian tube secretory epithelial cells (FT) to become pro-tumorigenic in mouse fallopian tubes. In addition, cisplatin efflux via exosomes was significantly increased in ovarian cancer cells under hypoxic conditions. Co-culture of HEx with tumor cells led to significantly decreased dsDNA damage and increased cell survival in response to cisplatin treatment. Blocking exosome release by known inhibitor Amiloride or STAT3 inhibitor and treating with cisplatin resulted in a significant increase in apoptosis, decreased colony formation, and proliferation. Our results demonstrate that HEx are more potent in augmenting metastasis/chemotherapy resistance in ovarian cancer and may serve as a novel mechanism for tumor metastasis, chemo-resistance, and a point of intervention for improving clinical outcomes.
MeSH term(s)	Animals ; Apoptosis/drug effects ; Apoptosis/physiology ; Cell Line, Tumor ; Cell Movement/drug effects ; Cell Movement/physiology ; Cell Proliferation/drug effects ; Cell Proliferation/physiology ; Cell Survival/drug effects ; Cell Survival/physiology ; Cisplatin/pharmacology ; Disease Progression ; Drug Resistance, Neoplasm/drug effects ; Drug Resistance, Neoplasm/physiology ; Exosomes/drug effects ; Exosomes/metabolism ; Exosomes/pathology ; Female ; Humans ; Hypoxia/drug therapy ; Hypoxia/metabolism ; Hypoxia/pathology ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Neoplasm Metastasis/pathology ; Ovarian Neoplasms/metabolism ; Ovarian Neoplasms/pathology ; Phenotype ; STAT3 Transcription Factor/metabolism ; rab GTP-Binding Proteins/metabolism
Chemical Substances	STAT3 Transcription Factor ; STAT3 protein, human ; rab GTP-Binding Proteins (EC 3.6.5.2) ; Cisplatin (Q20Q21Q62J)
Language	English
Publishing date	2018-04-11
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	639046-8
ISSN	1476-5594 ; 0950-9232
ISSN (online)	1476-5594
ISSN	0950-9232
DOI	10.1038/s41388-018-0189-0
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Zs.A 2218: Show issues

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Article ; Online: Cloning and characterization of the TneDI restriction: modification system of Thermotoga neapolitana.

Xu, Zhaohui / Han, Dongmei / Cao, Jingjing / Saini, Uksha

Extremophiles : life under extreme conditions

2011 Volume 15, Issue 6, Page(s) 665–672

Abstract: A putative Type II restriction-modification system of Thermotoga neapolitana, TneDI, was cloned into Escherichia coli XL1-Blue MRF' and characterized. Gene CTN_0339 specifies the endonuclease R.TneDI, while CTN_0340 encodes the cognate DNA ... ...

Abstract	A putative Type II restriction-modification system of Thermotoga neapolitana, TneDI, was cloned into Escherichia coli XL1-Blue MRF' and characterized. Gene CTN_0339 specifies the endonuclease R.TneDI, while CTN_0340 encodes the cognate DNA methyltransferase M.TneDI. Both enzymes were purified simply by heating the cell lysates of E. coli followed by centrifugation. The enzymes were active over a broad range of temperatures, from 42°C to at least 77°C, with the highest activities observed at 77°C. R.TneDI cleaved at the center of the recognition sequence (CG↓CG) and generated blunt-end cuts. Overexpression of R.TneDI in BL21(DE3) was confirmed by both SDS-PAGE and Western blotting.
MeSH term(s)	Base Sequence ; Blotting, Western ; Cloning, Molecular ; DNA Modification Methylases/metabolism ; DNA Primers ; Electrophoresis, Polyacrylamide Gel ; Escherichia coli/genetics ; Escherichia coli/growth & development ; Recombination, Genetic ; Thermotoga neapolitana/enzymology ; Thermotoga neapolitana/genetics
Chemical Substances	DNA Primers ; DNA Modification Methylases (EC 2.1.1.-)
Language	English
Publishing date	2011-09-15
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1481278-2
ISSN	1433-4909 ; 1431-0651
ISSN (online)	1433-4909
ISSN	1431-0651
DOI	10.1007/s00792-011-0397-9
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Article ; Online: STAT3/PIAS3

Saini, Uksha / Suarez, Adrian A / Naidu, Shan / Wallbillich, John J / Bixel, Kristin / Wanner, Ross A / Bice, Jason / Kladney, Raleigh D / Lester, Jenny / Karlan, Beth Y / Goodfellow, Paul J / Cohn, David E / Selvendiran, Karuppaiyah

Cancer research

2018 Volume 78, Issue 7, Page(s) 1739–1750

Abstract: The initial molecular events that lead to malignant transformation of the fimbria of the fallopian tube (FT) through high-grade serous ovarian carcinoma (HGSC) remain poorly understood. In this study, we report that increased expression of signal ... ...

Abstract	The initial molecular events that lead to malignant transformation of the fimbria of the fallopian tube (FT) through high-grade serous ovarian carcinoma (HGSC) remain poorly understood. In this study, we report that increased expression of signal transducer and activator of transcription 3 (
MeSH term(s)	Animals ; Cell Line, Tumor ; Cell Movement ; Cell Transformation, Neoplastic/genetics ; Cystadenocarcinoma, Serous/genetics ; Cystadenocarcinoma, Serous/pathology ; Fallopian Tube Neoplasms/genetics ; Fallopian Tube Neoplasms/pathology ; Fallopian Tubes/pathology ; Female ; Humans ; Mice ; Molecular Chaperones/genetics ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/pathology ; Precancerous Conditions/genetics ; Precancerous Conditions/pathology ; Protein Inhibitors of Activated STAT/genetics ; Proto-Oncogene Proteins c-myc/metabolism ; STAT3 Transcription Factor/genetics ; STAT3 Transcription Factor/metabolism ; Tumor Suppressor Protein p53/genetics
Chemical Substances	MYC protein, human ; Molecular Chaperones ; PIAS3 protein, human ; Protein Inhibitors of Activated STAT ; Proto-Oncogene Proteins c-myc ; STAT3 Transcription Factor ; STAT3 protein, human ; TP53 protein, human ; Tumor Suppressor Protein p53
Language	English
Publishing date	2018-01-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
DOI	10.1158/0008-5472.CAN-17-1671
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Article ; Online: Preconditioning mesenchymal stem cells with caspase inhibition and hyperoxia prior to hypoxia exposure increases cell proliferation.

Saini, Uksha / Gumina, Richard J / Wolfe, Brian / Kuppusamy, M Lakshmi / Kuppusamy, Periannan / Boudoulas, Konstantinos Dean

Journal of cellular biochemistry

2013 Volume 114, Issue 11, Page(s) 2612–2623

Abstract: Myocardial infarction is a leading cause of mortality and morbidity worldwide. Occlusion of a coronary artery produces ischemia and myocardial necrosis that leads to left ventricular (LV) remodeling, dysfunction, and heart failure. Stem cell therapy may ... ...

Abstract	Myocardial infarction is a leading cause of mortality and morbidity worldwide. Occlusion of a coronary artery produces ischemia and myocardial necrosis that leads to left ventricular (LV) remodeling, dysfunction, and heart failure. Stem cell therapy may decrease infarct size and improve LV function; the hypoxic environment, however, following a myocardial infarction may result in apoptosis, which in turn decreases survival of transplanted stem cells. Therefore, the effects of preconditioned mesenchymal stem cells (MSC) with hyperoxia (100% oxygen), Z-VAD-FMK pan-caspase inhibitor (CI), or both in a hypoxic environment in order to mimic conditions seen in cardiac tissue post-myocardial infarction were studied in vitro. MSCs preconditioned with hyperoxia or CI significantly decreased apoptosis as suggested by TUNEL assay and Annexin V analysis using fluorescence assisted cell sorting. These effects were more profound when both, hyperoxia and CI, were used. Additionally, gene and protein expression of caspases 1, 3, 6, 7, and 9 were down-regulated significantly in MSCs preconditioned with hyperoxia, CI, or both, while the survival markers Akt1, NF-κB, and Bcl-2 were significantly increased in preconditioned MSCs. These changes ultimately resulted in a significant increase in MSC proliferation in hypoxic environment as determined by BrdU assays compared to MSCs without preconditioning. These effects may prove to be of great clinical significance when transplanting stem cells into the hypoxic myocardium of post-myocardial infarction patients in order to attenuate LV remodeling and improve LV function.
MeSH term(s)	Amino Acid Chloromethyl Ketones/pharmacology ; Animals ; Caspase 1/genetics ; Caspase 1/metabolism ; Caspase 3/genetics ; Caspase 3/metabolism ; Caspase 6/genetics ; Caspase 6/metabolism ; Caspase 7/genetics ; Caspase 7/metabolism ; Caspase 9/genetics ; Caspase 9/metabolism ; Cell Hypoxia/physiology ; Cell Proliferation/drug effects ; Cells, Cultured ; Male ; Mesenchymal Stem Cells/cytology ; Mesenchymal Stem Cells/drug effects ; Mesenchymal Stem Cells/enzymology ; Rats
Chemical Substances	Amino Acid Chloromethyl Ketones ; benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone ; Casp3 protein, rat (EC 3.4.22.-) ; Casp6 protein, rat (EC 3.4.22.-) ; Casp9 protein, rat (EC 3.4.22.-) ; Caspase 3 (EC 3.4.22.-) ; Caspase 6 (EC 3.4.22.-) ; Caspase 7 (EC 3.4.22.-) ; Caspase 9 (EC 3.4.22.-) ; Caspase 1 (EC 3.4.22.36)
Language	English
Publishing date	2013-06-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	392402-6
ISSN	1097-4644 ; 0730-2312
ISSN (online)	1097-4644
ISSN	0730-2312
DOI	10.1002/jcb.24609
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Zs.A 1114: Show issues

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Article ; Online: High Glucose-Mediated STAT3 Activation in Endometrial Cancer Is Inhibited by Metformin

John J Wallbillich / Srirama Josyula / Uksha Saini / Roman A Zingarelli / Kalpana Deepa Priya Dorayappan / Maria K Riley / Ross A Wanner / David E Cohn / Karuppaiyah Selvendiran

PLoS ONE, Vol 12, Iss 1, p e

Therapeutic Implications for Endometrial Cancer.

2017 Volume 0170318

Abstract: STAT3 is over-expressed in endometrial cancer, and diabetes is a risk factor for the development of type 1 endometrial cancer. We therefore investigated whether glucose concentrations influence STAT3 expression in type 1 endometrial cancer, and whether ... ...

Abstract	STAT3 is over-expressed in endometrial cancer, and diabetes is a risk factor for the development of type 1 endometrial cancer. We therefore investigated whether glucose concentrations influence STAT3 expression in type 1 endometrial cancer, and whether such STAT3 expression might be inhibited by metformin.In Ishikawa (grade 1) endometrial cancer cells subjected to media with low, normal, or high concentrations of glucose, expression of STAT3 and its target proteins was evaluated by real-time quantitative PCR (qPCR). Ishikawa cells were treated with metformin and assessed with cell proliferation, survival, migration, and ubiquitin assays, as well as Western blot and qPCR. Expression of apoptosis proteins was evaluated with Western blot in Ishikawa cells transfected with a STAT3 overexpression plasmid and treated with metformin. A xenograft tumor model was used for studying the in vivo efficacy of metformin.Expression of STAT3 and its target proteins was increased in Ishikawa cells cultured in high glucose media. In vitro, metformin inhibited cell proliferation, survival and migration but induced apoptosis. Metformin reduced expression levels of pSTAT3 ser727, total STAT3, and its associated cell survival and anti-apoptotic proteins. Additionally, metformin treatment was associated with increased degradation of pSTAT3 ser727. No change in apoptotic protein expression was noticed with STAT3 overexpression in Ishikawa cells. In vivo, metformin treatment led to a decrease in tumor weight as well as reductions of STAT3, pSTAT3 ser727, its target proteins.These results suggest that STAT3 expression in type 1 endometrial cancer is stimulated by a high glucose environment and inhibited by metformin.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2017-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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