Autophagy is a self-degradation process by which cells consume parts of themselves to survive starvation and stress.In established tumors autophagy may fulfill the metabolic needs of cancer cells during oncogene activation or nutrient limitation by providing a mechanism to recycle intracellular carbon and nitrogen.The efficacy of autophagy inhibition in cancer therapy is well documented in preclinical models, and the lysosomotropic autophagy inhibitors chloroquine (CQ) and its analog, hydroxychloroquine (HCQ), are currently being evaluated in numerous cancer clinical trials1.However, different cancer cells present a different sensitivity toward these autophagy inhibitors,underscoring the need for additional compounds.We recently revealed that REV-ERBβ, a nuclear receptor involved in circadian rhythm and metabolism,is predominantly expressed in a number of cancer cell lines and primary rumors of different origins2.Using combined molecular genetic and pharmacological approaches, we showed that REV-ERBβ plays an unexpected role in sustaining cancer cell survival when the autophagy flux is pharmacologically or genetically compromised.These findings also resulted in the discovery of a novel class of cancer-specific cytotoxic compounds with a dual inhibitory activity toward REV-ERBβ and autophagy,which provides a scaffold for the development of new multifunctional anti-cancer agents2.Furthermore,these dual REV-ERB/autophagy inhibitors represent a valuable pharmacological tool for studies aimed to elucidate novel crosstalk between circadian rhythm, metabolism and autophagy that can determine cancer cell fate3.Implicit in this view is the concept that the altered circadian regulation found in several tumors may be triggered by the special metabolic needs of the cancer cell.Thus far, we obtained promising preliminary results indicating a REV-ERBβ-mediated regulation of glucose and lipid metabolism, two processes that play a prominent role in supporting energy production in cancer cells and that have been shown to be altered upon autophagy inhibition.These results provide an excellent gateway to explore the cancer metabolic signaling controlled by REV-ERBβ that may cooperate with the autophagy process in supporting prostate cancer cell viability.In addition, these studies may reveal additional avenues for the development of novel multi-targeted therapies of cancer.