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, Eunhee Kim, Kyeong Sook Choi

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number48
JournalCell Death and Disease
Volume15
Issue number1
DOIs
StatePublished - Jan 2024

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Cancer Research
  • Cell Biology
  • Immunology

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