HSP90 promotes cell glycolysis, proliferation and inhibits apoptosis by regulating PKM2 abundance via Thr-328 phosphorylation in hepatocellular carcinoma

Molecular Cancer

Research

Jianfeng Tu¹  Jun Zhang²  Lijie Li³  Kefeng Lei⁴  Changwei Dou⁵  Zhikui Liu⁵  Kangsheng Tu⁵  Yufeng Wang⁵  Xin Liu⁶  Qiuran Xu⁷  Liu Yang⁷  Jiahui Wang⁸  Hangxing Bao⁹ 

[1] Department of Emergency, Zhejiang Provincial People’s Hospital (People’s Hospital of Hangzhou Medical College), 310014, Hangzhou, Zhejiang, China;Department of Gastroenterology, Zhejiang Provincial People’s Hospital (People’s Hospital of Hangzhou Medical College), 310014, Hangzhou, Zhejiang, China;Department of General Surgery, Zhejiang Provincial People’s Hospital (People’s Hospital of Hangzhou Medical College), 310014, Hangzhou, Zhejiang, China;Department of Gynecology, Zhejiang Provincial People’s Hospital (People’s Hospital of Hangzhou Medical College), 310014, Hangzhou, Zhejiang, China;Department of Hepatobiliary Surgery, the First Affiliated Hospital of Xi’an Jiaotong University, 710061, Xi’an, Shaanxi, China;Department of Neurosurgery, Zhejiang Provincial People’s Hospital (People’s Hospital of Hangzhou Medical College), 310014, Hangzhou, Zhejiang, China;Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People’s Hospital (People’s Hospital of Hangzhou Medical College), 310014, Hangzhou, Zhejiang, China;School of Basic Medical Sciences, Shandong University, 250000, Jinan, Shandong, China;Zhejiang Hospital of Traditional Chinese Medical, 310006, Hangzhou, Zhejiang, China;

关键词: Hepatocellular carcinoma;    HSP90;    PKM2;    Glycolysis;    Growth;   

DOI  :  10.1186/s12943-017-0748-y

 received in 2017-08-01, accepted in 2017-12-05,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundHeat shock protein 90 (HSP90) functions as a well-known onco-protein to regulate protein conformation, stability and degradation. Pyruvate kinase M2 (PKM2), a critical regulator of the metabolism, growth and metastasis of cancer cells, has been confirmed to be overexpressed in various human cancer including hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying the oncogenic functions of HSP90 and PKM2 overexpression in HCC remain unknown.MethodsThe expression of HSP90 and PKM2 in HCC specimens and cells were detected by immunoblotting and immunostaining. The interaction between HSP90 and PKM2 was confirmed by tandem affinity purification, co-immunoprecipitation and Glutathione S transferase (GST)-pulldown assay.ResultsIn this study, we found that HSP90 could bind to PKM2 and subsequently increased PKM2 abundance in HCC cells. Immunohistochemistry (IHC) staining showed that HSP90 level was positively correlated with PKM2 level in HCC tissues. Mechanistically, HSP90 was found to increase the phosphorylation of PKM2 at Thr-328. Protein kinase glycogen synthase kinase-3β (GSK-3β) formed a protein complex with HSP90 and PKM2, and directly mediated Thr-328 phosphorylation of PKM2 induced by HSP90. Thr-328 phosphorylation was critical for maintaining PKM2 stability and its biological functions in regulating glycolysis, mitochondria respiration, proliferation and apoptosis. Functionally, we found that HSP90 promoted the glycolysis and proliferation and inhibited apoptosis of HCC cells in a PKM2 dependent manner. In vivo experiments disclosed that PKM2 was required for the promoting effects of HSP90 on the growth of HCC cells in mice. Furthermore, we demonstrated that positive expression of HSP90 and PKM2 was correlated with poor clinicopathological features including high alpha fetoprotein (AFP) level, large tumor size, portal vein tumor thrombus (PVTT) and advanced tumor-node-metastasis (TNM) stage. Furthermore, we demonstrated that positive expression of HSP90 and PKM2, and a combination of these proteins could strongly predict the poor prognosis of HCC patients.ConclusionsWe suggest that HSP90 potentiates the glycolysis and proliferation, reduces the apoptosis and thus enhances the growth of HCC cells through PKM2.

【 授权许可】

CC BY   
© The Author(s). 2017