SHP-1 is a target of regorafenib in colorectal cancer

Abstract

// Li-Ching Fan 1,2,* , Hao-Wei Teng 3,4,* , Chung-Wai Shiau 5,* , Hang Lin 1,2 , Man-Hsin Hung 3,6 , Yen-Lin Chen 7 , Jui-Wen Huang 8 , Wei-Tien Tai 1,2 , Hui-Chuan Yu 1,2 and Kuen-Feng Chen 1,2 1 Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan 2 National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan 3 Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan 4 National Yang-Ming University School of Medicine, Taipei, Taiwan 5 Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan 6 Program in Molecular Medicine, School of Life Sciences, National Yang-Ming University, Taipei, Taiwan 7 Department of Pathology, Cardinal Tien Hospital, School of Medicine, Fu-Jen Catholic University, New Taipei, Taiwan 8 Industrial Technology Research Institute, Hsin-Chu, Taiwan * These authors contributed equally to this work Correspondence: Kuen-Feng Chen, email: // Keywords : SHP-1, Regorafenib, Colorectal cancer, STAT3, Apoptosis Received : April 10, 2014 Accepted : July 8, 2014 Published : July 9, 2014 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.