Abstract 4724: Anti-tumor effects of SC-2001, a novel STAT3 inhibitor, in breast cancer cells

Abstract

Abstract Background: STAT3 has been shown to play an important role in breast carcinogenesis and is often overexpressed in primary breast tumors. STAT3 has emerged as a novel potential anti-cancer target. Previously, we have designed SC-2001 ((Z)-2-((3-methoxy-2H-pyrrol-2-ylidene)methyl)-1H-pyrrole) and reported its efficacy in HCC cells (AACR 2011, abstract#4516). SC-2001 is structurally related to the Mcl-1 inhibitor obatoclax, and showed better antitumor effects than obatoclax in HCC cells. Here, we examined the efficacy and drug mechanism of SC-2001 in breast cancer cells. Methods: breast cancer cell lines were used for in vitro studies. Apoptosis was examined by both flow cytometry and Western blot. Signal transduction pathways in cells were assessed by Western Blot. Tyrosine Phosphatase Assay Kit was used for SHP-1 activity assay. Gene silencing was done by small interference RNA (siRNA). Results: SC-2001 inhibited tumor cell growth (by MTT assay) and induced apoptosis in several breast cancer cell lines (MDA MB-468, MDA MB-231, MDA MB-453, MCF-7). SC-2001 inhibited the protein-protein interactions between Mcl-1 and Bak similar to obatoclax. In addition, SC-2001 downregulated Mcl-1 expression by reducing its transcription, whereas obatoclax had no such effect. SC-2001 downregulated the phosphorylation of STAT3 (Tyr 705) and subsequently inhibited its transcriptional activities in a dose-dependent manner. Moreover, STAT3-regulated proteins, including Mcl-1, survivin and cyclin D1, were also repressed by SC-2001. Over-expression of STAT3 in MDA MB-468 cells protected cells from SC-2001-induced apoptosis. Importantly, SC-2001 enhanced the expression of SHP-1, a negative regulator of STAT3. Inhibition of SHP-1 by either specific inhibitor or siRNA reduced the apoptotic effects of SC-2001, indicating that SHP-1 plays a key role in mediating SC-2001-induced cell death. Conclusions: our results suggest that SC-2001 induced apoptosis in breast cancer cells, and that this effect is mediated through SHP-1-dependent STAT3 inactivation. (Supported by NSC100-2325-B-002-036, NSC98-2320-B-010-005-My3 and NSC-100-2325-B-010-007, VGHTPE V100D-005-4, 101DHA0100318, and 101DHA0100230.) Keyword: obatoclax, breast cancer, STAT3, SHP-1, apoptosis Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4724. doi:1538-7445.AM2012-4724