SH2 domain-containing phosphatase 1 regulates pyruvate kinase M2 in hepatocellular carcinoma
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Wei-Tien Tai1,2, Man-Hsin Hung3,4,9, Pei-Yi Chu5,6, Yao-Li Chen7,10, Li-Ju Chen1,2, Ming-Hsien Tsai1,2, Min-Husan Chen1,2, Chung-Wai Shiau8, Yin-Pin Boo1,2, Kuen-Feng Chen1,2
1Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
2National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan
3Division of Meidcal Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan
4Program in Molecular Medicine, School of Life Science, National Yang-Ming University, Taipei, Taiwan
5Department of Pathology, Show Chwan Memorial Hospital, Changhua City, Taiwan
6School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan
7Department of Surgery, Changhua Christian Hospital, Changhua, Taiwan
8Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan
9School of Medicine, National Yang-Ming University, Taipei, Taiwan
10School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
Kuen-Feng Chen, e-mail: [email protected]
Keywords: PKM2, SHP-1, PTPN6, sorafenib, HCC
Received: August 20, 2015 Accepted: February 23, 2016 Published: March 5, 2016
Pyruvate kinase M2 (PKM2) is known to promote tumourigenesis through dimer formation of p-PKM2Y105. Here, we investigated whether SH2-containing protein tyrosine phosphatase 1 (SHP-1) decreases p-PKM2Y105 expression and, thus, determines the sensitivity of sorafenib through inhibiting the nuclear-related function of PKM2. Immunoprecipitation and immunoblot confirmed the effect of SHP-1 on PKM2Y105 dephosphorylation. Lactate production was assayed in cells and tumor samples to determine whether sorafenib reversed the Warburg effect. Clinical hepatocellular carcinoma (HCC) tumor samples were assessed for PKM2 expression. SHP-1 directly dephosphorylated PKM2 at Y105 and further decreased the proliferative activity of PKM2; similar effects were found in sorafenib-treated HCC cells. PKM2 was also found to determine the sensitivity of targeted drugs, such as sorafenib, brivanib, and sunitinib, by SHP-1 activation. Significant sphere-forming activity was found in HCC cells stably expressing PKM2. Clinical findings suggest that PKM2 acts as a predicting factor of early recurrence in patients with HCC, particularly those without known risk factors (63.6%). SHP-1 dephosphorylates PKM2 at Y105 to inhibit nuclear function of PKM2 and determines the efficacy of targeted drugs. Targeting PKM2 by SHP-1 might provide new therapeutic insights for patients with HCC.
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