INVESTIGATING REGULATORS OF AUTOPHAGY

Abstract

Misregulation of autophagy has been recognized to result in cancer; hence manipulation of autophagy has very important therapeutic implications. In our studies, inhibition of ICMT has been found to result in the induction of autophagy, which enhances cell death in some cancer cells. From siRNA-mediated knockdown of a group of ICMT substrates, the Rac3 GTPase was identified as a negative regulator of autophagy, but not its closely related isoforms Rac1 and Rac2. Moreover, in the current study, FoxO3a was found to be a negative regulator of autophagy in multiple cancer cell lines, a previously unrecognized function for this protein, different from its function in benign fibroblast and muscle cells. Interestingly, the regulatory role of FoxO3a on autophagy was determined to be through its ability to transcriptionally suppress FoxO1. Taken together, these studies will provide us not only novel information to better understand the autophagy process, but also the therapeutic targets in autophagy for cancer treatment.