The Antipsychotic Drug Aripiprazole Suppresses Colorectal Cancer by Targeting LAMP2a to Induce RNH1/miR‐99a/mTOR‐Mediated Autophagy and Apoptosis

Abstract

The mammalian target of rapamycin (mTOR) is a critical signaling hub for sustaining cancer survival. Targeting mTOR and inducing autophagic cell death downstream of it represent promising therapeutic strategies for cancer prevention. A US Food and Drug Administration-approved drug library containing 616 small molecules is used to screen anticancer drugs against colorectal cancer (CRC) cells that rely on mTOR. This led to the identification of an antipsychotic drug aripiprazole, which significantly induced mTOR inhibition and autophagic apoptosis in CRC, in vitro and in vivo. The use of drug affinity response target stability identified lysosome-associated membrane protein 2A (LAMP2a) as a direct target of aripiprazole. LAMP2a-deficient CRC cells are refractory to aripiprazole. High LAMP2a expression is associated with poor survival of patients with CRC and negatively correlated with expression of ribonuclease inhibitor 1 (RNH1), which is later confirmed as a novel substrate of LAMP2a. Mechanistically, aripiprazole bound to the Lys401–His404 of LAMP2a and repressed its activity, subsequently inactivating RNH1/miR-99a/mTOR signaling and inducing autophagy-mediated apoptosis, thereby suppressing tumorigenesis. Liposome-mediated delivery of aripiprazole in combination with fluorouracil elicited superior therapeutic benefits in CRC, as compared to single treatments, thereby highlighting that aripiprazole may be repurposed as a novel therapeutic agent for CRC treatment.