detalle del documento
IDENTIFICACIÓN
doi:10.1038/s41419-024-06434-x...
Autor
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 SookLangue
enEditor
Nature
Categoría
Life Sciences
Año
2024
fecha de cotización
17/1/2024
Palabras clave
akt cancer paraptosisResumen
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.
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, 2024, Akt enhances the vulnerability of cancer cells to VCP/p97 inhibition-mediated paraptosis, Nature
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