Abstract 678: SOCS-1 inhibits proliferation of ovarian cancer cell lines by regulating JAK/STAT3 pathway and p53

Abstract

Abstract [BACKGROUND]Ovarian cancer (OC) is a leading cause of the gynecological malignancy death in United States and many developed nations, and the number of OC patients is increasing. Patients with OC have poor prognosis because most OCs are detected at late stage and they often recur after chemotherapy with chemoresistance. So we need novel therapies for refractory OC. Recently, lines of evidence showed that constitutive activation of IL-6/JAK/STAT3 (signal transducers and activators of transcription 3) pathway is involved in proliferation of many kinds of cancer, including OC. SOCS (suppressor of cytokine signaling) families are known as negative regulators of JAK /STAT signal pathway. The aim of this study is to evaluate the effect of SOCS-1 in proliferation of OC and to develop a new therapy for intractable OC. [MATERIAL and METHOD]We overexpressed SOCS-1 in ten human OC cell lines (MCAS, OVISE, OVCAR-3, OVSAHO, OVTOKO, OVMANA, ES-2, A2780, SKOV-3, RMG-1) by infecting cells with adenovirus vector expressing SOCS-1. Adenovirus vector expressing LacZ was used as a control. Anti-proliferative effect of SOCS-1 in OC was assessed by WST-8 assay. Proteins related to apoptosis and other signal pathways were assessed by Western blot analysis. The interaction between SOCS-1 and p53 was examined by immunoprecipitation assays. [RESULT] Overexpression of SOCS-1 inhibited proliferation of 9 OC cell lines. Significantly enhanced apoptosis was observed in these cell lines. In most cell lines, STAT3 pathway was constitutively activated and was downregulated by SOCS-1 overexpression. However, growth inhibition by SOCS-1 was also observed in cell lines in which STAT3 activation at baseline was hardly detectable. Our screening analyses indicated that AKT, FAK and p44/p42 MAPK pathways were not affected by overexpression of SOCS-1. Finally, we found that in cell lines possessing wild type p53, overexpressed SOCS-1 associated with p53 and increased its protein levels. In contrast, JAK inhibitor failed to influence p53 expression. [Conclusion]SOCS-1 inhibited proliferation of OC cell lines by regulating JAK/STAT3 pathway and interacting with p53. SOCS-1 contributed to the enhancement of the stability and/or transcription activity of p53. In addition, signal pathways other than JAK/STAT3 and p53 pathways seemed to be regulated by SOCS-1. Now we analyze these unidentified signal pathways which may be regulated by SOCS-1 in OC. Citation Format: Satoshi Nakagawa, Satoshi Serada, Yusuke Takahashi, Yutaka Ueda, Minoru Fujimoto, Kiyoshi Yoshino, Takayuki Enomoto, Tadashi Kimura, Tetsuji Naka. SOCS-1 inhibits proliferation of ovarian cancer cell lines by regulating JAK/STAT3 pathway and p53. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 678. doi:10.1158/1538-7445.AM2015-678