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Erschienen in: Breast Cancer Research and Treatment 1/2014

01.07.2014 | Preclinical study

Obatoclax analog SC-2001 inhibits STAT3 phosphorylation through enhancing SHP-1 expression and induces apoptosis in human breast cancer cells

verfasst von: Chun-Yu Liu, Jung-Chen Su, Mei-Huei Ni, Ling-Ming Tseng, Pei-Yi Chu, Duen-Shian Wang, Wei-Tien Tai, Yuan-Ping Kao, Man-Hsin Hung, Chung-Wai Shiau, Kuen-Feng Chen

Erschienen in: Breast Cancer Research and Treatment | Ausgabe 1/2014

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Abstract

Interfering oncogenic STAT3 signaling is a promising anti-cancer strategy. We examined the efficacy and drug mechanism of an obatoclax analog SC-2001, a novel STAT3 inhibitor, in human breast cancer cells. Human breast cancer cell lines were used for in vitro studies. Apoptosis was examined by both flow cytometry and western blot. Signaling pathways were assessed by western blot. In vivo efficacy of SC-2001 was tested in xenograft nude mice. SC-2001 inhibited cell growth and induced apoptosis in association with downregulation of p-STAT3 (Tyr 705) in breast cancer cells. STAT3-regulated proteins, including Mcl-1, survivin, and cyclin D1, were repressed by SC-2001. Over-expression of STAT3 in MDA-MB-468 cells protected cells from SC-2001-induced apoptosis. Moreover, SC-2001 enhanced the expression of protein tyrosine phosphatase SHP-1, a negative regulator of STAT3. Furthermore, the enhanced SHP-1 expression, in conjunction with increased SHP-1 phosphatase activity, was mediated by upregulated transcription by RFX-1. Chromatin immunoprecipitation assay revealed that SC-2001 increased the binding capacity of RFX-1 to the SHP-1 promoter. Knockdown of either RFX-1 or SHP-1 reduced SC-2001-induced apoptosis, whereas ectopic expression of RFX-1 increased SHP-1 expression and enhanced the apoptotic effect of SC-2001. Importantly, SC-2001 suppressed tumor growth in association with enhanced RFX-1 and SHP-1 expression and p-STAT3 downregulation in MDA-MB-468 xenograft tumors. SC-2001 induced apoptosis in breast cancer cells, an effect that was mediated by RFX-1 upregulated SHP-1 expression and SHP-1-dependent STAT3 inactivation. Our study indicates targeting STAT3 signaling pathway may be a useful approach for the development of targeted agents for anti-breast cancer.
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Metadaten
Titel
Obatoclax analog SC-2001 inhibits STAT3 phosphorylation through enhancing SHP-1 expression and induces apoptosis in human breast cancer cells
verfasst von
Chun-Yu Liu
Jung-Chen Su
Mei-Huei Ni
Ling-Ming Tseng
Pei-Yi Chu
Duen-Shian Wang
Wei-Tien Tai
Yuan-Ping Kao
Man-Hsin Hung
Chung-Wai Shiau
Kuen-Feng Chen
Publikationsdatum
01.07.2014
Verlag
Springer US
Erschienen in
Breast Cancer Research and Treatment / Ausgabe 1/2014
Print ISSN: 0167-6806
Elektronische ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-014-3000-0

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