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- Title
Akt enhances the vulnerability of cancer cells to VCP/p97 inhibition-mediated paraptosis.
- Authors
Lee, Dong Min; Kim, In Young; Lee, Hong Jae; Seo, Min Ji; Cho, Mi-Young; Lee, Hae In; Yoon, Gyesoon; Ji, Jae-Hoon; Park, Seok Soon; Jeong, Seong-Yun; Choi, Eun Kyung; Choi, Yong Hyeon; Yun, Chae-Ok; Yeo, Mirae; Kim, Eunhee; Choi, Kyeong Sook
- 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.
- Publication
Cell Death & Disease, 2024, Vol 15, Issue 1, p1
- ISSN
2041-4889
- Publication type
Article
- DOI
10.1038/s41419-024-06434-x