The Antipsychotic Drug Aripiprazole Suppresses Colorectal Cancer by Targeting LAMP2a to Induce...

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• The mammalian target of rapamycin (mTOR) pathway is crucial for cancer cell survival.
• Targeting mTOR and inducing autophagic cell death are potential cancer therapeutic strategies.

Purpose of the Study:

• To screen for novel anticancer drugs targeting mTOR in colorectal cancer (CRC).
• To investigate the potential repurposing of existing drugs for CRC treatment.

Main Methods:

• Screening of a 616-drug library against mTOR-dependent CRC cells.
• In vitro and in vivo validation of drug efficacy.
• Drug affinity response target stability (DARTS) to identify drug targets.
• Analysis of LAMP2a expression and its correlation with patient survival and RNH1.

Main Results:

• Aripiprazole identified as an inducer of mTOR inhibition and autophagic apoptosis in CRC cells.
• Lysosome-associated membrane protein 2A (LAMP2a) identified as a direct target of aripiprazole.
• LAMP2a deficiency renders CRC cells resistant to aripiprazole.
• High LAMP2a expression correlates with poor CRC patient survival and reduced RNH1.
• Aripiprazole represses LAMP2a activity, inactivating RNH1/miR-99a/mTOR signaling and inducing apoptosis.
• Combination therapy with liposome-mediated aripiprazole and fluorouracil showed superior therapeutic effects.

Conclusions:

• Aripiprazole demonstrates significant anticancer activity in colorectal cancer by targeting the LAMP2a/RNH1/miR-99a/mTOR axis.
• LAMP2a is a direct target of aripiprazole and plays a critical role in its efficacy.
• Aripiprazole holds potential for repurposing as a novel therapeutic agent for colorectal cancer treatment, particularly in combination therapies.