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

Abstract

// Wen Hu 1, 2, * , Shi-Xun Lu 1, 2, * , Min Li 1, 2 , Chao Zhang 1, 2 , Li-Li Liu 1, 2 , Jia Fu 1, 2 , Jie-Tian Jin 1, 2 , Rong-Zhen Luo 1, 2 , Chris Zhiyi Zhang 1, 2 , Jing-Ping Yun 1, 2 1 Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China 2 Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China * These authors have contributed equally to this work Correspondence to: Chris Zhiyi Zhang, e-mail: zhangzhy@sysucc.org.cn Jing-Ping Yun, e-mail: yunjp@sysucc.org.cn Keywords: PKM2, Bim, apoptosis, hepatocellular carcinoma Received: December 26, 2014      Accepted: January 30, 2015      Published: March 02, 2015 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.