Pyruvate kinase M2 prevents apoptosis via modulating Bim stability and associates with poor outcome in hepatocellular carcinoma.

Wen Hu,Rong-Zhen Luo,Shi-Xun Lu,Li-Li Liu,Chris Zhiyi Zhang,Jie-Tian Jin,Chao Zhang,Min Li,Jing-Ping Yun,Jia Fu

doi:10.18632/oncotarget.3262

Abstract

Pyruvate kinase M2 (PKM2) contributes to the Warburg effect, a hallmark of cancer. We showed that PKM2 levels were correlated with overall survival (hazard ration = 1.675, 95% confidence interval: 1.389-2.019, P < 0.001) and disease-free survival (hazard ration = 1.573, 95% confidence interval: 1.214-2.038, P < 0.001) in a cohort of 490 patients with HCC. The correlations were further validated in an independent cohort of 148 HCC patients. Multivariate analyses revealed that PKM2 was an independent indicator of poor outcome in HCC. The knockdown of PKM2 in HCC cells inhibited cell proliferation and induced apoptosis in vitro and in vivo. Bim siRNA markedly abolished the PKM2-depletion-induced apoptosis. PKM2 depletion decreased the degradation of Bim. In clinical samples, PKM2 expression was reversely correlated with Bim expression. Combination of PKM2 and Bim levels had the best prognostic significance. We suggest that PKM2 serves as a promising biomarker for poor prognosis of patients with HCC and its knockdown induces HCC apoptosis by stabilizing Bim.

Highlights

Pyruvate kinase M2 (PKM2) is a rate-limiting enzyme in the process of transferring phosphoenolpyruvate (PEP) and ADP to pyruvate and ATP, respectively [1]
We suggest that PKM2 serves as a promising biomarker for poor prognosis of patients with HCC and its knockdown induces HCC apoptosis by stabilizing Bim
PKM2 has been demonstrated to be notably upregulated in various types of cancers and responsible for their poor prognosis, such as gastric cancer [20] and prostate cancer [21]

Summary

Introduction

Pyruvate kinase M2 (PKM2) is a rate-limiting enzyme in the process of transferring phosphoenolpyruvate (PEP) and ADP to pyruvate and ATP, respectively [1]. PKM2 contributes to the Warburg effect [2]. Previous studies demonstrated that PKM2 was mainly expressed in well-differentiated tissues [3]. Overexpression of PKM2 was detected in a various types of cancer, such as glioma [4] and tongue tumor [5]. Zhang et al showed that high PKM2 expression was associated with shorter overall survival in esophageal squamous cell cancer [6]. Up-regulation of PKM2 in hepatocellular carcinoma has been recently reported [7, 8]

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