Akt enhances the vulnerability of cancer cells to VCP/p97 inhibition-mediated paraptosis

Abstract Valosin-containing protein (VCP)/p97, an AAA + ATPase that plays a pivotal role in proteostasis, is a potential therapeutic target for cancer. We report that targeting VCP preferentially kills breast cancer cells over non-transformed cells by inducing paraptosis, a non-apoptotic cell death mode accompanied by the endoplasmic reticulum and mitochondria dilation. We also found that the expression of oncogenic HRas sensitizes non-transformed cells to VCP inhibition-mediated paraptosis. The preferential vulnerability of cancer cells to VCP inhibition is associated with the non-attenuation and recovery of protein synthesis under proteotoxic stress. Mechanistically, mTORC2/Akt activation and eIF3d-dependent translation contribute to this translational recovery and proteotoxic stress enhancement. Additionally, the ATF4/DDIT4 axis enhances VCP inhibition-mediated paraptosis by activating Akt. Considering that hyperactive Akt counteracts chemotherapeutic-induced apoptosis, VCP inhibition may offer a therapeutic opportunity to exploit Akt-associated vulnerability in cancer cells by inducing paraptosis, sparing normal cells.