Targeting the Warburg effect in cancer cells through ENO1 knockdown rescues oxidative phosphorylation and induces growth arrest

• Published in: Oncotarget 2016-02, Vol.7 (5), p.5598-5612
• Main Authors: Capello, Michela, Ferri-Borgogno, Sammy, Riganti, Chiara, Chattaragada, Michelle Samuel, Principe, Moitza, Roux, Cecilia, Zhou, Weidong, Petricoin, Emanuel F, Cappello, Paola, Novelli, Francesco
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Autophagy; Biomarkers, Tumor - antagonists & inhibitors; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Blotting, Western; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Cycle; Cell Proliferation; Cellular Reprogramming; DNA-Binding Proteins - antagonists & inhibitors; DNA-Binding Proteins - genetics; Female; Humans; Mice; Mice, SCID; Oxidative Phosphorylation; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Phosphopyruvate Hydratase - antagonists & inhibitors; Phosphopyruvate Hydratase - genetics; Proteomics; Reactive Oxygen Species - metabolism; Real-Time Polymerase Chain Reaction; Research Paper; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Small Interfering - genetics; Signal Transduction; Tandem Mass Spectrometry; Tumor Cells, Cultured; Tumor Suppressor Proteins - antagonists & inhibitors; Tumor Suppressor Proteins - genetics; Xenograft Model Antitumor Assays
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.6798

In the last 5 years, novel knowledge on tumor metabolism has been revealed with the identification of critical factors that fuel tumors. Alpha-enolase (ENO1) is commonly over-expressed in tumors and is a clinically relevant candidate molecular target for immunotherapy. Here, we silenced ENO1 in human cancer cell lines and evaluated its impact through proteomic, biochemical and functional approaches. ENO1 silencing increased reactive oxygen species that were mainly generated through the sorbitol and NADPH oxidase pathways, as well as autophagy and catabolic pathway adaptations, which together affect cancer cell growth and induce senescence. These findings represent the first comprehensive metabolic analysis following ENO1 silencing. Inhibition of ENO1, either alone, or in combination with other pathways which were perturbed by ENO1 silencing, opens novel avenues for future therapeutic approaches.