Pharmacological targeting SHP-1-STAT3 signaling is a promising therapeutic approach for the treatment of colorectal cancer

Li Ching Fan, Hao Wei Teng, Chung Wai Shiau, Wei Tien Tai, Man Hsin Hung, Shung Haur Yang, Jeng Kai Jiang, Kuen Feng Chen*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

STAT3 activation is associated with poor prognosis in human colorectal cancer (CRC).Our previous data demonstrated that regorafenib (Stivarga) is a pharmacological agonist of SH2 domain-containing phosphatase 1 (SHP-1) that enhances SHP-1 activity and induces apoptosis by targeting STAT3 signals in CRC. This study aimed to find a therapeutic drug that is moreeffective than regorafenib for CRC treatment. Here, we showed that SC-43 was more effective than regorafenib at inducing apoptosis in vitro and suppressing tumorigenesis in vivo. SC-43 significantly increased SHP-1 activity, downregulated p-STAT3Tyr705 level, and induced apoptosis in CRC cells. An SHP-1 inhibitor or knockdown of SHP-1 by siRNA both significantly rescued the SC-43-induced apoptosis and decreased p-STAT3Tyr705 level. Conversely, SHP-1 overexpression increased the effects of SC-43 on apoptosis and p-STAT3Tyr705 level. These data suggest that SC-43-induced apoptosis mediated through the loss of p-STAT3Tyr705 was dependent on SHP-1 function. Importantly, SC-43-enhanced SHP-1 activity was because of the docking potential of SC-43, which relieved the autoinhibited N--SH2 domain of SHP-1 and inhibitedp-STAT3Tyr705 signals. Importantly, we observed that a significant negative correlation existed between SHP-1 and p-STAT3Tyr705expression in CRC patients (P = .038). Patients with strong SHP-1 and weak p-STAT3Tyr705 expression had significantly higher overall survival compared with patients with weak SHP-1 and strong p-STAT3Tyr705 expression (P = .029). In conclusion, SHP-1 is suitable to be a useful prognostic marker and a pharmacological target for CRC treatment. Targeting SHP-1-STAT3 signaling by SC-43 may serve as a promising pharmacotherapy for CRC.

Original languageEnglish
Pages (from-to)687-696
Number of pages10
JournalNeoplasia
Volume17
Issue number9
DOIs
StatePublished - 2015

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