Energy metabolic block induces accelerated senescence in human cancer cells

Abstract

Glycolytic pathway is an essential source of energy in cancer cells; therefore, it can be selectively targeted by anticancer pharmacotherapy. The pivotal enzyme in this pathway is glyceraldehyde 3‐phosphate dehydrogenase (GAPDH) which executes both enzymatic and regulatory functions. We evaluated the role of GAPDH in the control of energy homeostasis in isogenic (p53+/+ and p53−/−) human carcinoma cells by using RNA interference, site mutagenesis, and confocal microscopy. Knockdown of GAPDH induced accelerated senescence of cancer cells via p53‐regulated pathway, in the absence of DNA damage. Depletion of GAPDH by short interfering RNA decreased protein level, GAPDH enzymatic activity, and ATP. In response to reduced ATP, AMPK pathway was activated leading to p53 stabilization, and cell proliferation arrest. GAPDH‐depleted cells acquired senescence phenotype revealed by changes in morphology and senescence‐associated markers. Rescue experiments aimed to reinstate energy metabolism (by adding the downstream metabolite pyruvate), or GAPDH level partially restored ATP level but not cell proliferation suggesting that energy crisis by GAPDH depletion may not be the only cause of accelerated senescence. These results indicate that accelerated senescence induced by GAPDH depletion may provide a strategy to control proliferation of cancer cells.This work was supported in part by NCI grant R01 CA104729.