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Targeting constitutively-activated STAT3 in hypoxic ovarian cancer, using a novel STAT3 inhibitor
Tumor hypoxia, a feature of many solid tumors including ovarian cancer, is associated with resistance to therapies. We previously demonstrated that hypoxic exposure results in increased expression of phosphorylated signal transducer and activator of transcription 3 (pSTAT3). We hypothesized the acti...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4278289/ https://www.ncbi.nlm.nih.gov/pubmed/25594014 |
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author | McCann, Georgia A. Naidu, Shan Rath, Kellie S. Bid, Hemant K. Tierney, Brent J. Suarez, Adrian Varadharaj, Saradhadevi Zhang, Jianying Hideg, Kálmán Houghton, Peter Kuppusamy, Periannan Cohn, David E. Selvendiran, Karuppaiyah |
author_facet | McCann, Georgia A. Naidu, Shan Rath, Kellie S. Bid, Hemant K. Tierney, Brent J. Suarez, Adrian Varadharaj, Saradhadevi Zhang, Jianying Hideg, Kálmán Houghton, Peter Kuppusamy, Periannan Cohn, David E. Selvendiran, Karuppaiyah |
author_sort | McCann, Georgia A. |
collection | PubMed |
description | Tumor hypoxia, a feature of many solid tumors including ovarian cancer, is associated with resistance to therapies. We previously demonstrated that hypoxic exposure results in increased expression of phosphorylated signal transducer and activator of transcription 3 (pSTAT3). We hypothesized the activation of STAT3 could lead to chemotherapeutic resistance in ovarian cancer cells in hypoxic conditions. In this study, we demonstrate the level of pSTAT3 Tyr705 is increased in the hypoxic regions of human epithelial ovarian cancer (EOC) specimens, as determined by HIF-1α and CD-31 staining. In vitro mutagenesis studies proved that pSTAT3 Tyr705 is necessary for cell survival and proliferation under hypoxic conditions. In addition, we show that S1PR1, a regulator of STAT3 transcription via the JAK/STAT pathway, is highly expressed in hypoxic ovarian cancer cells (HOCCs). Knock down of S1PR1 in HOCCs reduced pSTAT3 Tyr705 levels and was associated with decreased cell survival. Treatment of HOCCs with the STAT3 inhibitor HO-3867 resulted in a rapid and dramatic decrease in pSTAT3 Tyr705 levels as a result of ubiquitin proteasome degradation. STAT3-target proteins Bcl-xL, cyclin D2 and VEGF showed similar decreases in HO-3867 treated cells. Taken together, these findings suggest that activation of STAT3 Tyr705 promotes cell survival and proliferation in HOCCs, and that S1PR1 is involved in the initiation of STAT3 activation. Targeting hypoxia-mediated STAT3 activation represents a therapeutic option for ovarian cancer and other solid tumors. |
format | Online Article Text |
id | pubmed-4278289 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-42782892015-01-15 Targeting constitutively-activated STAT3 in hypoxic ovarian cancer, using a novel STAT3 inhibitor McCann, Georgia A. Naidu, Shan Rath, Kellie S. Bid, Hemant K. Tierney, Brent J. Suarez, Adrian Varadharaj, Saradhadevi Zhang, Jianying Hideg, Kálmán Houghton, Peter Kuppusamy, Periannan Cohn, David E. Selvendiran, Karuppaiyah Oncoscience Research Paper Tumor hypoxia, a feature of many solid tumors including ovarian cancer, is associated with resistance to therapies. We previously demonstrated that hypoxic exposure results in increased expression of phosphorylated signal transducer and activator of transcription 3 (pSTAT3). We hypothesized the activation of STAT3 could lead to chemotherapeutic resistance in ovarian cancer cells in hypoxic conditions. In this study, we demonstrate the level of pSTAT3 Tyr705 is increased in the hypoxic regions of human epithelial ovarian cancer (EOC) specimens, as determined by HIF-1α and CD-31 staining. In vitro mutagenesis studies proved that pSTAT3 Tyr705 is necessary for cell survival and proliferation under hypoxic conditions. In addition, we show that S1PR1, a regulator of STAT3 transcription via the JAK/STAT pathway, is highly expressed in hypoxic ovarian cancer cells (HOCCs). Knock down of S1PR1 in HOCCs reduced pSTAT3 Tyr705 levels and was associated with decreased cell survival. Treatment of HOCCs with the STAT3 inhibitor HO-3867 resulted in a rapid and dramatic decrease in pSTAT3 Tyr705 levels as a result of ubiquitin proteasome degradation. STAT3-target proteins Bcl-xL, cyclin D2 and VEGF showed similar decreases in HO-3867 treated cells. Taken together, these findings suggest that activation of STAT3 Tyr705 promotes cell survival and proliferation in HOCCs, and that S1PR1 is involved in the initiation of STAT3 activation. Targeting hypoxia-mediated STAT3 activation represents a therapeutic option for ovarian cancer and other solid tumors. Impact Journals LLC 2014-03-31 /pmc/articles/PMC4278289/ /pubmed/25594014 Text en © 2014 McCann et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper McCann, Georgia A. Naidu, Shan Rath, Kellie S. Bid, Hemant K. Tierney, Brent J. Suarez, Adrian Varadharaj, Saradhadevi Zhang, Jianying Hideg, Kálmán Houghton, Peter Kuppusamy, Periannan Cohn, David E. Selvendiran, Karuppaiyah Targeting constitutively-activated STAT3 in hypoxic ovarian cancer, using a novel STAT3 inhibitor |
title | Targeting constitutively-activated STAT3 in hypoxic ovarian cancer, using a novel STAT3 inhibitor |
title_full | Targeting constitutively-activated STAT3 in hypoxic ovarian cancer, using a novel STAT3 inhibitor |
title_fullStr | Targeting constitutively-activated STAT3 in hypoxic ovarian cancer, using a novel STAT3 inhibitor |
title_full_unstemmed | Targeting constitutively-activated STAT3 in hypoxic ovarian cancer, using a novel STAT3 inhibitor |
title_short | Targeting constitutively-activated STAT3 in hypoxic ovarian cancer, using a novel STAT3 inhibitor |
title_sort | targeting constitutively-activated stat3 in hypoxic ovarian cancer, using a novel stat3 inhibitor |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4278289/ https://www.ncbi.nlm.nih.gov/pubmed/25594014 |
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