Akt enhances the vulnerability of cancer cells to VCP/p97 inhibition-mediated paraptosis
Dong Min Lee, In Young Kim, Hong Jae Lee, Min Ji Seo, Mi-Young Cho, Hae In Lee, Gyesoon Yoon, Jae‐Hoon Ji, Seok Soon Park, Seong‐Yun Jeong, Eun Kyung Choi, Yong Hyeon Choi, Chae‐Ok Yun, Mirae Yeo, Eun Hee Kim, Kyeong Sook Choi
Abstract
Valosin-containing protein (VCP)/p97, an AAA+ ATPase critical for maintaining proteostasis, emerges as a promising target for cancer therapy. This study reveals that targeting VCP selectively eliminates breast cancer cells while sparing non-transformed cells by inducing paraptosis, a non-apoptotic cell death mechanism characterized by endoplasmic reticulum and mitochondria dilation. Intriguingly, oncogenic HRas sensitizes non-transformed cells to VCP inhibition-mediated paraptosis. The susceptibility of cancer cells to VCP inhibition is attributed to the non-attenuation and recovery of protein synthesis under proteotoxic stress. Mechanistically, mTORC2/Akt activation and eIF3d-dependent translation contribute to translational rebound and amplification of proteotoxic stress. Furthermore, the ATF4/DDIT4 axis augments VCP inhibition-mediated paraptosis by activating Akt. Given that hyperactive Akt counteracts chemotherapeutic-induced apoptosis, VCP inhibition presents a promising therapeutic avenue to exploit Akt-associated vulnerabilities in cancer cells by triggering paraptosis while safeguarding normal cells.