title: Targeting constitutively-activated STAT3 in hypoxic ovarian cancer, using a novel STAT3 inhibitor.
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-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.
authors.affiliation: Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH.
authors.forename: Georgia A
authors.initials: GA
authors.lastname: McCann
authors.affiliation: Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH.
authors.forename: Shan
authors.initials: S
authors.lastname: Naidu
authors.affiliation: Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH.
authors.forename: Kellie S
authors.initials: KS
authors.lastname: Rath
authors.affiliation: Nationwide Children's Hospital, Columbus, OH.
authors.forename: Hemant K
authors.initials: HK
authors.lastname: Bid
authors.affiliation: Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH.
authors.forename: Brent J
authors.initials: BJ
authors.lastname: Tierney
authors.affiliation: Department of Pathology, Divisions of Gynecological Pathology and Cytopathology, The Ohio State University Wexner Medical Center, Columbus, OH.
authors.forename: Adrian
authors.initials: A
authors.lastname: Suarez
authors.affiliation: Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH.
authors.forename: Saradhadevi
authors.initials: S
authors.lastname: Varadharaj
authors.affiliation: Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH.
authors.forename: Jianying
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Institute of Organic and Medicinal Chemistry, University of Pécs, Pécs, Hungary.
authors.forename: Kálmán
authors.initials: K
authors.lastname: Hideg
authors.affiliation: Nationwide Children's Hospital, Columbus, OH.
authors.forename: Peter
authors.initials: P
authors.lastname: Houghton
authors.affiliation: Department of Radiology, The Dartmouth Medical School, Hanover, NH.
authors.forename: Periannan
authors.initials: P
authors.lastname: Kuppusamy
authors.affiliation: Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH.
authors.forename: David E
authors.initials: DE
authors.lastname: Cohn
authors.affiliation: Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH.
authors.forename: Karuppaiyah
authors.initials: K
authors.lastname: Selvendiran
keywords: Chemo-resistance; HO-3867; Hypoxia; Ovarian Cancer; STAT3