Dual PI3K/mTOR inhibitor PKI-402 suppresses the growth of ovarian cancer cells by degradation of Mcl-1 through autophagy.

The phosphoinositide 3-kinase (PI3K) /AKT/mammalian target of rapamycin (mTOR) signaling pathway is frequently mutated in cancers, leading to increased cell proliferation, migration, and chemoresistance. Currently, a number of small molecule inhibitors of the PI3K/AKT/mTOR signaling pathway have been assessed in preclinical and clinical studies. It has been found that dual PI3K/mTOR inhibitors may inhibit cell proliferation and induce apoptosis in cancers, but the mechanism is still being explored. Therefore, determining the role of dual PI3K/mTOR inhibitors PKI-402 in cancer cells may facilitate overcoming chemoresistance. By referring to a gene database and screening gene sequences, we found that human ovarian cancer epithelial cell lines SKOV3 and A2780 had mutations of the PIK3CA gene, which might be relatively sensitive to dual-targeted PI3K/mTOR inhibitors. In this study, our data indicated that dual PI3K/mTOR inhibitor PKI-402 disrupted the balance of Bcl-2 family proteins by degrading the Mcl-1 protein through autophagy. Moreover, the autophagy receptor protein p62 bound to Mcl-1 through its ubiquitin-associated domain (UBA domain) to participate in the degradation of Mcl-1 through autophagy. This offers hope for the treatment of ovarian cancer patients with mutations of the PI3K/AKT/mTOR pathway.