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 twodimensional 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.

GLUT3 upregulation promotes metabolic reprogramming associated with antiangiogenic therapy resistance

“…These models yielded important distinct findings compared with previous studies, such as our finding of unchanged number of mitochondria in resistant versus sensitive xenografts, a finding that contrasts with reports of decreased mitochondria in bevacizumab-treated xenografts (17,18). These findings suggest that a recovery of mitochondrial mass lost during initial treatment occurs during the evolution of resistance to antiangiogenic therapy despite persistent functional impairment of these mitochondria.…”

VEGF-Targeted Therapy Stably Modulates the Glycolytic Phenotype of Tumor Cells

“…In this respect, it has been reported that glucose deprivation provides a strong selection for activated oncogenes, such as KRAS (42). Moreover, Xu and colleagues recently described mitochondrial defects in ex vivo cultures of LoVo cells from bevacizumab-treated tumors (43), and we also found reduced mitochondrial mass and decreased expression of NDUFS1, a component of respiratory complex I, in ex vivo cultures of bevacizumab-treated IGROV-1 cells (Supplementary Fig. S5).…”

Endothelial cell metabolism: parallels and divergences with cancer cell metabolism

“…As a result, cancer cells turn more to non-oxidative metabolism, which could contribute to the selection of resistant cancer clones [21]. A compelling observation is that antiangiogenic treatment can induce persistent metabolic changes in cancer cells (i.e., suppression of mitochondrial biogenesis and hyperactive glycolysis) [22]. Whether this reflects epigenetic reprogramming of metabolism with long-lasting effects is unknown but certainly deserves investigation.…”