Novel sorafenib analogues induce apoptosis through SHP-1 dependent STAT3 inactivation in human breast cancer cells

Abstract

IntroductionSignal transducers and activators of transcription 3 (STAT3) signaling is constitutively activated in various cancers including breast cancer and has emerged as a novel potential anti-cancer target. STAT3 has been demonstrated to be a target of sorafenib, and a protein tyrosine phosphatase Src homology 2-domain containing tyrosine phosphatase 1 (SHP-1) has been demonstrated to downregulate p-STAT3 via its phosphatase activity. Here, we tested the efficacy of two sorafenib analogues, SC-1 and SC-43, in breast cancer cells and examined the drug mechanism.MethodsBreast cancer cell lines were used for in vitro studies. Cell viability was examined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis was examined by flow cytometry and western blot. Signal transduction pathways in cells were assessed by western blot. In vivo efficacy of sorafenib, SC-1 and SC-43 was tested in xenografted nude mice.ResultsSC-1 and SC-43 induced more potent apoptosis than sorafenib, in association with downregulation of p-STAT3 and its downstream proteins cyclin D1 and survivin in a dose-dependent manner in breast cancer cell lines (HCC-1937, MDA-MB-468, MDA-MB-231, MDA-MB-453, SK-BR3, MCF-7). Overexpression of STAT3 in MDA-MB-468 cells protected the cells from apoptosis induced by sorafenib, SC-1 and SC-43. Moreover, SC-1 and SC-43 upregulated SHP-1 activity to a greater extent than sorafenib as measured by in vitro phosphatase assays. Knockdown of SHP-1 by siRNA reduced apoptosis induced by SC-1 and SC-43. Importantly, SC-1 and SC-43 showed more efficacious antitumor activity and p-STAT3 downregulation than sorafenib in MDA-MB-468 xenograft tumors.ConclusionsNovel sorafenib analogues SC-1 and SC-43 induce apoptosis through SHP-1 dependent STAT3 inactivation and demonstrate greater potency than sorafenib in human breast cancer cells.

SHP-1 is a target of regorafenib in colorectal cancer

“…We also provided the first evidence demonstrating that regorafenib is a novel enhancer of SHP-1 tyrosine phosphatase activity, which dramatically decreases p-STAT3 Tyr705 expression. Ample evidence suggests that SHP-1 functions as a tumor suppressor that directly targets the oncogenic expression of p-STAT3 Tyr705 that is crucial for the tumor survival and cellular proliferation [6, 21-24]. Our study demonstrated for the first time that regorafenib activated an SHP-1 tumor suppression pathway by directly enhancing SHP-1 activity, and induced apoptosis and tumor suppression in CRC.…”

“…Importantly, our previous studies have clearly demonstrated that SHP-1 is a negative regulator of p-STAT3 Tyr705 [6, 21-24] that is highly expressed in cancer cells and is crucial for growth, survival, and metastasis of cancer cells during cancer progression. Therefore, we clarify whether the sorafenib analog regorafenib (Fluoro-sorafenib) acts as a direct enhancer of SHP-1 by which enhanced SHP-1 activity directly downregulates p-STAT3 Tyr705 and eventually contributes to apoptosis in CRC.…”

Sorafenib induces cathepsin B-mediated apoptosis of bladder cancer cells by regulating the Akt/PTEN pathway. The Akt inhibitor, perifosine, enhances the sorafenib-induced cytotoxicity against bladder cancer cells.

“…Sorafenib has been shown to activate various PTPs in different cell types [14,30-32]. Herein, the effect of sorafenib on SHP-1 and/or PTEN activation was evaluated in BC cells via western blot analysis.…”

Promotion of Cancer Stem-Like Cell Properties in Hepatitis C Virus-Infected Hepatocytes

“…Sorafenib is used for HCC treatment, although it is effective for only a short time. SC-1 inhibits Stat3 phosphorylation and induces apoptosis in a breast cancer cell line (31). We treated cells with sorafenib (multikinase inhibitor, including c-Kit) and/or stattic (Stat3 inhibitor).…”