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

• DOI: 10.1038/s41419-024-06434-x
• Publication Date: 2024-01-13T14:01:44Z
• Authors: 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; Eunhee Kim; Kyeong Sook Choi
• Keywords: Proteostasis; Synthetic Lethality

Valosin-containing protein (VCP)/p97, an AAA+ ATPase critical for maintaining proteostasis, emerges as a promising target cancer therapy. This study reveals that targeting VCP selectively eliminates breast cells while sparing non-transformed by inducing paraptosis, non-apoptotic cell death mechanism characterized endoplasmic reticulum and mitochondria dilation. Intriguingly, oncogenic HRas sensitizes to inhibition-mediated paraptosis. The susceptibility of inhibition is attributed the non-attenuation recovery synthesis under proteotoxic stress. Mechanistically, mTORC2/Akt activation eIF3d-dependent translation contribute translational rebound amplification Furthermore, ATF4/DDIT4 axis augments paraptosis activating Akt. Given hyperactive Akt counteracts chemotherapeutic-induced apoptosis, presents therapeutic avenue exploit Akt-associated vulnerabilities in triggering safeguarding normal cells.