Abstract B27: RIP1 maintains DNA integrity and cell proliferation by regulating PGC-1α-mediated mitochondrial oxidative phosphorylation and glycolysis

Abstract

Abstract In the presence of ample oxygen, cancer cells prefer glycolysis to mitochondrial respiration for energy supply. This metabolic alteration, known as the Warburg effect or aerobic glycolysis, has been shown to contribute to cancer cell proliferation. However, how this glucose metabolism pathway is precisely regulated remains elusive. Receptor-interacting protein 1 (RIP1) is an important cellular signaling molecule that plays a pivotal role in the regulation of cell death, survival and proliferation. However, the role of RIP1 in cell metabolism is unclear. To investigate the function of RIP1 in lung cancer cell proliferation, we established stable RIP1 knockdown lung cancer cell lines using lentivius-mediated shRNA expression. RIP1 knockdown inhibited the proliferation of lung cancer cells, which was associated with DNA damage-induced p53 activation. Compared with control cells, the RIP1 knockdown cells had higher glucose consumption and lactate production, indicating a higher glycolytic rate. The increased glycolysis lowered the cellular level of nicotinamide adenine dinucleotide (NAD+), a cofactor essential for DNA damage repair. By microarray profiling and promoter reporter assays, we determined that RIP1 positively regulates the expression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), a key factor involved in the regulation of mitochondrial function. The downregulation of PGC-1α reduced the expression of components of electron transfer chain that impaired oxidative phosphorylation, which underlays the increased glycolysis in RIP1 knockdown cells. Moreover, RIP1 knockdown cells were more sensitive to both DNA damage anticancer agents and glycolysis inhibitors. Our data suggest that while aerobic glycolysis within a certain range favors cancer cell proliferation, excessive glycolysis may cause cytostasis. Thus, maintenance of glycolysis by RIP1 is critical to cancer cell energy homeostasis and DNA integrity, which may be exploited for anticancer therapy. Citation Format: Wenshu Chen, Qiong Wang, Lang Bai, Weijie Chen, Xia Wang, Carmen S. Tellez, Shuguang Leng, Mabel T. Padilla, Toru Nyunoya, Steven A. Belinsky, Yong Lin. RIP1 maintains DNA integrity and cell proliferation by regulating PGC-1α-mediated mitochondrial oxidative phosphorylation and glycolysis. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr B27.