PKM2 promotes tumor angiogenesis by regulating HIF-1α through NF-κB activation

Molecular Cancer

Research

Alexander Becher¹  Kristina Diepold¹  Ninel Azoitei¹  Thomas Seufferlein¹  Arefeh Rouhi²  Konrad Steinestel³  Felicitas Genze⁴  Thomas Simmet⁴ 

[1] Center for Internal Medicine I, University of Ulm, Albert-Einstein-Allee 23, 89081, Ulm, Germany;Center for Internal Medicine III, University of Ulm, 89081, Ulm, Germany;Gerhard-Domagk-Institute of Pathology, University of Münster, 48149, Münster, Germany;Institute of Pharmacology of Natural Products & Clinical Pharmacology, University of Ulm, 89081, Ulm, Germany;

关键词: Pancreatic cancer;    Tumor growth;    Tumor angiogenesis;    Apoptosis;    Hypoxia;    PKM2;    p65/RelA;    HIF-1α;    CAM;   

DOI  :  10.1186/s12943-015-0490-2

 received in 2015-07-29, accepted in 2015-12-29,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundInitially identified as a molecule that regulates the final step of glycolysis, the M2 isoform of pyruvate kinase (PKM2) was recently reported to have a central role in the metabolic reprogramming of cancer cells as well as participating in cell cycle progression and gene transcription. Despite intensive efforts, the intricate molecular mechanisms through which PKM2 regulates tumor progression remain elusive.MethodsThe proliferation and apoptosis of various pancreatic cancer cells using lentiviral-mediated PKM2 abrogation were assessed in vitro via Western blot and flow cytometric assay while the in vivo experiments involved tumor xenograft on chicken chorionallantoic membranes and immunohistochemistry on human tissue specimens. In order to decipher the molecular mechanism of HIF-1α and p65/RelA regulation by PKM2 in cancer cells cultivated in hypoxic atmosphere or normoxia we involved various biochemical assays such as Western blotting, immunoprecipitation, reporter gene assay and ELISA.ResultsStrong expression of PKM2 was observed in 68 % of human pancreatic adenocarcinoma specimens and almost all analyzed pancreatic cancer cell lines. Abrogation of PKM2 resulted in impaired proliferation and augmented apoptosis in vitro as well as impaired tumor growth and decreased blood vessel formation in vivo. Furthermore, deletion of PKM2 negatively impacted hypoxia-induced HIF-1α accumulation and promoter activity ultimately resulting in impaired secretion of VEGF.ConclusionsOur study suggests that in hypoxic pancreatic tumors PKM2 interferes both with NF-κB/p65 and HIF-1α activation that ultimately triggers VEGF-A secretion and subsequent blood vessel formation.

【 授权许可】

CC BY   
© Azoitei et al. 2016