title: Colorectal cancer cells refractory to anti-VEGF treatment are vulnerable to glycolytic blockade due to persistent impairment of mitochondria.
abstract: Antiangiogenesis therapy has shed new light on cancer treatment, but its effectiveness, especially for overall patient survival, is still controversial. Here, we show that antiangiogenesis treatment causes a persistent suppression of mitochondria biogenesis in colorectal cancer cells, which renders them more sensitive to glycolytic blockade therapy. We first analyzed bevacizumab-resistant colon cancer xenografts by two-dimensional Blue Native/SDS-PAGE and found a serious and persistent loss of mitochondrial protein complex I. Further metabolic assays revealed significantly impaired mitochondrial function and hyperactive glycolysis, which were concomitant with the upregulation of HIF-1 and Hsp70. The treatment of bevacizumab-resistant cells with the glycolysis inhibitor 3-BrPA caused cell senescence in vitro. Intraperitoneal injection of 3-BrPA to xenograft mice bearing bevacizumab-resistant cells also resulted in smaller tumor volume and longer survival. These data provide direct evidence for the mitochondrial destruction of bevacizumab-resistant tumor cells and suggest that glycolysis blockade may potentiate the therapeutic effect of antiangiogenesis treatment.
authors: State Key Laboratory for Oncogenes and Related Genes, GI Division, Shanghai Jiao-Tong University School of Medicine Renji Hospital, Shanghai Institute of Digestive Disease, Shanghai, China. xujieletter@gmail.com
authors: Jie
authors: J
authors: Xu
authors: Jilin
authors: J
authors: Wang
authors: Bin
authors: B
authors: Xu
authors: Haiyan
authors: H
authors: Ge
authors: Xiaolin
authors: X
authors: Zhou
authors: Jing-Yuan
authors: JY
authors: Fang
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000378:metabolism; D047368:Tumor Burden; D042442:Vascular Endothelial Growth Factors / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D042442:Vascular Endothelial Growth Factors