ATF4/NUPR1 axis promotes cancer cell survival and mediates immunosuppression in clear cell renal cell carcinoma.

Autor: Lu Y; People's Liberation Army Postgraduate Medical School, Fuxing Road 28, Haidian District, Beijing, 100853, China.; State Key Laboratory of Kidney Diseases, Senior Department of Urology, The Third Medical Center of Chinese PLA General Hospital, Yongding Road 69, Haidian District, Beijing, 100039, China., Chen W; People's Liberation Army Postgraduate Medical School, Fuxing Road 28, Haidian District, Beijing, 100853, China.; State Key Laboratory of Kidney Diseases, Senior Department of Urology, The Third Medical Center of Chinese PLA General Hospital, Yongding Road 69, Haidian District, Beijing, 100039, China., Xuan Y; People's Liberation Army Postgraduate Medical School, Fuxing Road 28, Haidian District, Beijing, 100853, China.; State Key Laboratory of Kidney Diseases, Senior Department of Urology, The Third Medical Center of Chinese PLA General Hospital, Yongding Road 69, Haidian District, Beijing, 100039, China., Li X; State Key Laboratory of Kidney Diseases, Senior Department of Urology, The Third Medical Center of Chinese PLA General Hospital, Yongding Road 69, Haidian District, Beijing, 100039, China., Wu S; People's Liberation Army Postgraduate Medical School, Fuxing Road 28, Haidian District, Beijing, 100853, China.; State Key Laboratory of Kidney Diseases, Senior Department of Urology, The Third Medical Center of Chinese PLA General Hospital, Yongding Road 69, Haidian District, Beijing, 100039, China., Wang H; People's Liberation Army Postgraduate Medical School, Fuxing Road 28, Haidian District, Beijing, 100853, China., Guo T; People's Liberation Army Postgraduate Medical School, Fuxing Road 28, Haidian District, Beijing, 100853, China., Wang C; People's Liberation Army Postgraduate Medical School, Fuxing Road 28, Haidian District, Beijing, 100853, China., Tian S; People's Liberation Army Postgraduate Medical School, Fuxing Road 28, Haidian District, Beijing, 100853, China., Li H; People's Liberation Army Postgraduate Medical School, Fuxing Road 28, Haidian District, Beijing, 100853, China.; State Key Laboratory of Kidney Diseases, Senior Department of Urology, The Third Medical Center of Chinese PLA General Hospital, Yongding Road 69, Haidian District, Beijing, 100039, China., Lai D; People's Liberation Army Postgraduate Medical School, Fuxing Road 28, Haidian District, Beijing, 100853, China., Zhao W; People's Liberation Army Postgraduate Medical School, Fuxing Road 28, Haidian District, Beijing, 100853, China., Huang X; People's Liberation Army Postgraduate Medical School, Fuxing Road 28, Haidian District, Beijing, 100853, China., Zhao X; School of Medicine, Nankai University, Weijin Road 94, Tianjin, 300071, China., Wang B; State Key Laboratory of Kidney Diseases, Senior Department of Urology, The Third Medical Center of Chinese PLA General Hospital, Yongding Road 69, Haidian District, Beijing, 100039, China., Zhang X; State Key Laboratory of Kidney Diseases, Senior Department of Urology, The Third Medical Center of Chinese PLA General Hospital, Yongding Road 69, Haidian District, Beijing, 100039, China., Li H; State Key Laboratory of Kidney Diseases, Senior Department of Urology, The Third Medical Center of Chinese PLA General Hospital, Yongding Road 69, Haidian District, Beijing, 100039, China. urolancet@126.com., Huang Y; State Key Laboratory of Kidney Diseases, Senior Department of Urology, The Third Medical Center of Chinese PLA General Hospital, Yongding Road 69, Haidian District, Beijing, 100039, China. dr.huangyan301@foxmail.com., Ma X; State Key Laboratory of Kidney Diseases, Senior Department of Urology, The Third Medical Center of Chinese PLA General Hospital, Yongding Road 69, Haidian District, Beijing, 100039, China. mxin301@126.com.
Jazyk: angličtina
Zdroj: Discover oncology [Discov Oncol] 2024 Oct 31; Vol. 15 (1), pp. 607. Date of Electronic Publication: 2024 Oct 31.
DOI: 10.1007/s12672-024-01485-0
Abstrakt: Cancer cells encounter unavoidable stress during tumor growth. The stress-induced transcription factor, activating transcription factor 4 (ATF4), has been reported to upregulate various adaptive genes involved in salvage pathways to alleviate stress and promote tumor progression. However, this effect is unknown in clear cell renal cell carcinoma (ccRCC). In this study, we found that ATF4 expression was remarkably upregulated in tumor tissues and associated with poor ccRCC outcomes. ATF4 depletion significantly impaired ccRCC cell proliferation, migration, and invasion in vitro and in vivo by inhibiting the AKT/mTOR and epithelial-mesenchymal transition (EMT)-related signaling pathway. RNA sequencing and functional studies identified nuclear protein 1 (NUPR1) as a key downstream target of ATF4 for repressing ferroptosis and promoting ccRCC cell survival. In addition, targeting ATF4 or pharmacological inhibition using NUPR1 inhibitor ZZW115 promoted antitumor immunity in syngeneic graft mouse models, represented by increased infiltration of CD4 + and CD8 + T cells. Furthermore, ZZW115 could improve the response to the PD-1 immune checkpoint blockade. The results demonstrate that the ATF4/NUPR1 signaling axis promotes ccRCC survival and facilitates tumor-mediated immunosuppression, providing a set of potential targets and prognostic indicators for ccRCC patients.
(© 2024. The Author(s).)
Databáze: MEDLINE
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