Senescent cells develop PDK4-dependent hypercatabolism and form an acidic microenvironment to drive cancer resistance

Abstract

Abstract Cellular senescence is a state of stable growth arrest, usually accompanied by development of the senescence-associated secretory phenotype (SASP). Although senescent cells remain metabolically active, little is known about their metabolic landscape and in vivo pathophysiological implications. Here we show that expression of the pyruvate dehydrogenase (PDH) inhibitory enzyme, pyruvate dehydrogenase kinase 4 (PDK4), is significantly upregulated in human senescent stromal cells. Preferentially expressed upon genotoxicity-induced senescence (GIS), PDK4 is negatively correlated with posttreatment survival of cancer patients. Upon cellular senescence, PDK4 shifts glucose metabolic flux from oxidative phosphorylation to aerobic glycolysis, causing enhanced lactate production and forming an acidic microenvironment. However, distinct from the cancer cell-featured Warburg effect, senescent cells maintain an intensive use of pyruvate through the tricarboxylic acid cycle (TCA), displaying increased respiration and redox activity, indicative of a special form of metabolic reprogramming. Conditioned media from PDK4+ stromal cells change global expression and promote malignancy of recipient cancer cells in vitro and accelerate tumor progression in vivo. Pharmacologically targeting PDK4 restrains the adverse effects of PDK4 in cell-based assays, while promoting tumor regression and extending posttreatment survival in preclinical trials. Together, our study substantiates the hypercatabolic nature of senescent cells, and reveals a metabolic link between senescence-associated acidic microenvironment and age-related pathologies including but not limited to cancer.