A novel function of TIMP1/CD63 signaling in the regulation of tumor metabolism (LB68)

Abstract

A distinctive feature of cancer cells that sets them apart from normal non‐transformed cells is a unique metabolic profile. In the 1920s, Otto Warburg recognized that carcinogenesis was accompanied by a striking shift to glycolysis as the major energy‐generating pathway. Nearly a century later, it is still unclear if this “glycolytic switch” is an epiphenomenon or a mechanistic determinant for malignancy. During the course of studying tissue inhibitor of metalloproteinase (TIMP)‐1 signaling, we found that TIMP‐1 upregulates the rate of the aerobic glycolysis as evidenced by increased glucose uptake and lactate production. TIMP‐1 upregulated hexokinaseII RNA level, known to be the rate‐limiting step of glycolysis. Interestingly, TIMP‐1‐induced glycolysis was accompanied with reduced mitochondrial respiration as shown by reduced cytochrome c oxidase activity and a low rate of oxygen consumption. ShRNA‐mediated knockdown of the tetraspanin CD63, a cell surface binding partner of TIMP‐1, reversed the TIMP‐1‐mediated glycolytic switch. Interestingly, TIMP‐1 activation of the CD63 signaling complex resulted in constitutive activation of HIF1α and protected breast epithelial cells from hypoxia‐induced cell death. In contrast, TIMP‐1‐stimulated cells rapidly underwent cell death upon glucose withdrawal. Taken together, the present study demonstrates a novel function of TIMP‐1 in the regulation of tumor metabolism in a CD63‐dependent manner.