SHP-1 is a target of regorafenib in colorectal cancer.

Abstract

Regorafenib is an inhibitor of multiple protein kinases which exerts antitumor and antimetastatic activities in metastatic colorectal cancer (CRC). SH2 domain-containing phosphatase 1 (SHP-1) is reported to have tumor suppressive potential because it acts as a negative regulator of p-STAT3(Tyr705) signaling. However, little is known about the mechanism regarding regorafenib affects SHP-1 tyrosine phosphatase activity and leads to apoptosis and tumor suppression in CRC. Here, we found that regorafenib triggered apoptotic cell death and significantly enhanced SHP-1 activity, which dramatically decreased the phosphorylated form of STAT3 at Tyr705 (p-STAT3(Tyr705)). Importantly, regorafenib augmented SHP-1 activity by direct disruption of the association between N-SH2 and catalytic PTP domain of SHP-1. Deletion of the N-SH2 domain (dN1) or point mutation (D61A) of SHP-1 blocked the effect of regorafenib-induced SHP-1 activity, growth inhibition and a decrease of p-STAT3(Tyr705) expression, suggesting that regorafenib triggers a conformational change in SHP-1 by relieving its autoinhibition. In vivo assay showed that regorafenib significantly inhibited xenograft growth and decreased p-STAT3(Tyr705) expression but induced higher SHP-1 activity. Collectively, regorafenib is a novel SHP-1 agonist exerts superior anti-tumor effects by enhancing SHP-1 activity that directly targets p-STAT3(Tyr705). Small molecule-enhancement of SHP-1 activity may be a promising therapeutic approach for CRC treatment.

• Authors: Li-Ching Fan, Hao-Wei Teng, Chung-Wai Shiau, Hang Lin, Man-Hsin Hung, Yen-Lin Chen, Jui-Wen Huang, Wei-Tien Tai, Hui-Chuan Yu, Kuen-Feng Chen
• Journal: Oncotarget (Oncotarget) Vol. 5 Issue 15 Pg. 6243-51 (Aug 15 2014) ISSN: 1949-2553 [Electronic] United States
• PMID: 25071018 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Phenylurea Compounds
• Pyridines
• STAT3 Transcription Factor
• STAT3 protein, human
• regorafenib
• PTPN6 protein, human
• Protein Tyrosine Phosphatase, Non-Receptor Type 6

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Cell Growth Processes (drug effects)
• Colorectal Neoplasms (drug therapy, enzymology, metabolism, pathology)
• Down-Regulation
• HCT116 Cells
• HT29 Cells
• Humans
• Mice
• Mice, Nude
• Phenylurea Compounds (pharmacology)
• Protein Tyrosine Phosphatase, Non-Receptor Type 6 (metabolism)
• Pyridines (pharmacology)
• STAT3 Transcription Factor (metabolism)
• Signal Transduction (drug effects)
• Xenograft Model Antitumor Assays