Mitochondrial Carrier SLC25A13 Regulates Breast Cancer Cell Cycle

SLC25A12/SLC25A13 controls intracellular NADH state via its mitochondrial aspartate-glutamate transporter activity,as an essential component of NADH shuttle.For oxidative NAD~+,as a co-factor of a variety of enzymes,plays a vital role in tumorigenesis,SLC25A12 and SLC25A13 may have a broad range of effects on cancer.In this project,we found SLC25A13 is up-regulated in breast cancer tissue and high expression of SLC25A13 correlated with poor overall survival and breast cancer recurrence.With siRNA knockdown in MCF-7 cell line,in vitro experiments show down-regulation of SLC25A13 inhibits breast cancer cell growth as well as cell cycle progress.The G0/G1 phase arrest is caused by p27 protein level accumulation.CHX treatment experiment indicates that p27 accumulation is due to prolonged protein half-life instead of up-regulation of mRNA level.After SLC25A13knockdown,we could not observe MAPK signal activation,which is thought to be another reason for p27 accumulation.We also found SLC25A13 knockdown could induce Sirt2 protein level but not mRNA level,double-knockdown of SLC25A13 and Sirt2 with siRNA reverses p27 protein accumulation as well as cell cycle arrest induced by SLC25A13 interference.Furthermore,SLC25A13 could control cellular NADH state determined by using NAD~+/NADH fluorescent biosensor.Taken together,SLC25A13 regulates cell cycle via Sirt2-p27 pathway in breast cancer cell line.SLC25A13 is a promising clinical marker for breast cancer.