Targeting constitutively-activated STAT3 in hypoxic ovarian cancer, using a novel STAT3 inhibitor

Georgia A. McCann, Shan Naidu, Kellie S. Rath, Hemant K. Bid, Brent J. Tierney, Adrian Suarez, Saradhadevi Varadharaj, Jianying Zhang, Kálmán Hideg, Peter J Houghton, Periannan Kuppusamy, David E. Cohn, Karuppaiyah Selvendiran

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

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- 1a 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.

Original languageEnglish (US)
Pages (from-to)216-228
Number of pages13
JournalOncoscience
Volume1
Issue number3
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

Fingerprint

STAT3 Transcription Factor
Ovarian Neoplasms
Cell Survival
Cell Proliferation
Cyclin D2
Proteasome Endopeptidase Complex
Ubiquitin
Mutagenesis
Vascular Endothelial Growth Factor A
Neoplasms
Staining and Labeling
Therapeutics

Keywords

  • Chemo-resistance
  • HO-3867
  • Hypoxia
  • Ovarian cancer
  • STAT3

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

McCann, G. A., Naidu, S., Rath, K. S., Bid, H. K., Tierney, B. J., Suarez, A., ... Selvendiran, K. (2014). Targeting constitutively-activated STAT3 in hypoxic ovarian cancer, using a novel STAT3 inhibitor. Oncoscience, 1(3), 216-228. https://doi.org/10.18632/oncoscience.26

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 J; Kuppusamy, Periannan; Cohn, David E.; Selvendiran, Karuppaiyah.

In: Oncoscience, Vol. 1, No. 3, 01.01.2014, p. 216-228.

Research output: Contribution to journalArticle

McCann, GA, Naidu, S, Rath, KS, Bid, HK, Tierney, BJ, Suarez, A, Varadharaj, S, Zhang, J, Hideg, K, Houghton, PJ, Kuppusamy, P, Cohn, DE & Selvendiran, K 2014, 'Targeting constitutively-activated STAT3 in hypoxic ovarian cancer, using a novel STAT3 inhibitor', Oncoscience, vol. 1, no. 3, pp. 216-228. https://doi.org/10.18632/oncoscience.26
McCann, Georgia A. ; Naidu, Shan ; Rath, Kellie S. ; Bid, Hemant K. ; Tierney, Brent J. ; Suarez, Adrian ; Varadharaj, Saradhadevi ; Zhang, Jianying ; Hideg, Kálmán ; Houghton, Peter J ; Kuppusamy, Periannan ; Cohn, David E. ; Selvendiran, Karuppaiyah. / Targeting constitutively-activated STAT3 in hypoxic ovarian cancer, using a novel STAT3 inhibitor. In: Oncoscience. 2014 ; Vol. 1, No. 3. pp. 216-228.
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