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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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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
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author 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
author_facet 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
author_sort Tai, Wei-Tien
collection PubMed
description 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.
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spelling pubmed-50083552016-09-12 SH2 domain-containing phosphatase 1 regulates pyruvate kinase M2 in hepatocellular carcinoma 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 Oncotarget Research Paper 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. Impact Journals LLC 2016-03-05 /pmc/articles/PMC5008355/ /pubmed/26959741 http://dx.doi.org/10.18632/oncotarget.7923 Text en Copyright: © 2016 Tai et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
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
SH2 domain-containing phosphatase 1 regulates pyruvate kinase M2 in hepatocellular carcinoma
title SH2 domain-containing phosphatase 1 regulates pyruvate kinase M2 in hepatocellular carcinoma
title_full SH2 domain-containing phosphatase 1 regulates pyruvate kinase M2 in hepatocellular carcinoma
title_fullStr SH2 domain-containing phosphatase 1 regulates pyruvate kinase M2 in hepatocellular carcinoma
title_full_unstemmed SH2 domain-containing phosphatase 1 regulates pyruvate kinase M2 in hepatocellular carcinoma
title_short SH2 domain-containing phosphatase 1 regulates pyruvate kinase M2 in hepatocellular carcinoma
title_sort sh2 domain-containing phosphatase 1 regulates pyruvate kinase m2 in hepatocellular carcinoma
topic Research Paper
url 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
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