PML restrains p53 activity and cellular senescence in clear cell renal cell carcinoma.

Autor:	Simoni M; Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy., Menegazzi C; Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy., Fracassi C; Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy., Biffi CC; Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy.; Medical Advisor, Sanofi, Milan, Italy., Genova F; Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, Milan, Italy., Tenace NP; Department of Pathology, IRCCS San Raffaele Scientific Institute, Milan, Italy., Lucianò R; Department of Pathology, IRCCS San Raffaele Scientific Institute, Milan, Italy., Raimondi A; Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy., Tacchetti C; Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy.; Universita' Vita-Salute San Raffaele, Milan, Italy., Brugarolas J; Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Department of Internal Medicine, Division of Hematology/Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA., Mazza D; Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy., Bernardi R; Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy. bernardi.rosa@hsr.it.
Jazyk:	angličtina
Zdroj:	EMBO molecular medicine [EMBO Mol Med] 2024 Jun; Vol. 16 (6), pp. 1324-1351. Date of Electronic Publication: 2024 May 10.
DOI:	10.1038/s44321-024-00077-3
Abstrakt:	Clear-cell renal cell carcinoma (ccRCC), the major subtype of RCC, is frequently diagnosed at late/metastatic stage with 13% 5-year disease-free survival. Functional inactivation of the wild-type p53 protein is implicated in ccRCC therapy resistance, but the detailed mechanisms of p53 malfunction are still poorly characterized. Thus, a better understanding of the mechanisms of disease progression and therapy resistance is required. Here, we report a novel ccRCC dependence on the promyelocytic leukemia (PML) protein. We show that PML is overexpressed in ccRCC and that PML depletion inhibits cell proliferation and relieves pathologic features of anaplastic disease in vivo. Mechanistically, PML loss unleashed p53-dependent cellular senescence thus depicting a novel regulatory axis to limit p53 activity and senescence in ccRCC. Treatment with the FDA-approved PML inhibitor arsenic trioxide induced PML degradation and p53 accumulation and inhibited ccRCC expansion in vitro and in vivo. Therefore, by defining non-oncogene addiction to the PML gene, our work uncovers a novel ccRCC vulnerability and lays the foundation for repurposing an available pharmacological intervention to restore p53 function and chemosensitivity. (© 2024. The Author(s).)
Databáze:	MEDLINE
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