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SH2 domain-containing phosphatase 1 regulates pyruvate kinase M2 in hepatocellular carcinoma

Pyruvate kinase M2 (PKM2) is known to promote tumourigenesis through dimer formation of p-PKM2(Y105). Here, we investigated whether SH2-containing protein tyrosine phosphatase 1 (SHP-1) decreases p-PKM2(Y105) expression and, thus, determines the sensitivity of sorafenib through inhibiting the nuclea...

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Detalles Bibliográficos
Autores principales: Tai, Wei-Tien, Hung, Man-Hsin, Chu, Pei-Yi, Chen, Yao-Li, Chen, Li-Ju, Tsai, Ming-Hsien, Chen, Min-Husan, Shiau, Chung-Wai, Boo, Yin-Pin, Chen, Kuen-Feng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5008355/
https://www.ncbi.nlm.nih.gov/pubmed/26959741
http://dx.doi.org/10.18632/oncotarget.7923
Descripción
Sumario:Pyruvate kinase M2 (PKM2) is known to promote tumourigenesis through dimer formation of p-PKM2(Y105). Here, we investigated whether SH2-containing protein tyrosine phosphatase 1 (SHP-1) decreases p-PKM2(Y105) 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 PKM2(Y105) 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.