PLA2R1 promotes DNA damage and inhibits spontaneous tumor formation during aging.

Autor: Huna A; Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR 5286, Centre Léon Bérard, Université de Lyon, Lyon, France., Griveau A; Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR 5286, Centre Léon Bérard, Université de Lyon, Lyon, France., Vindrieux D; Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR 5286, Centre Léon Bérard, Université de Lyon, Lyon, France., Jaber S; Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR 5286, Centre Léon Bérard, Université de Lyon, Lyon, France., Flaman JM; Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR 5286, Centre Léon Bérard, Université de Lyon, Lyon, France., Goehrig D; Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR 5286, Centre Léon Bérard, Université de Lyon, Lyon, France., Azzi L; INSERM U1053 Bordeaux Research in Translational Oncology, University of Bordeaux, Bordeaux Cedex, France., Médard JJ; Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR 5286, Centre Léon Bérard, Université de Lyon, Lyon, France., Djebali S; Centre International de Recherche en Infectiologie, Inserm U1111, CNRS, UMR5308, École Normale Supérieure de Lyon, Université de Lyon, Université Claude Bernard Lyon 1, Lyon, France., Hernandez-Vargas H; Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR 5286, Centre Léon Bérard, Université de Lyon, Lyon, France., Dante R; Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR 5286, Centre Léon Bérard, Université de Lyon, Lyon, France., Payen L; Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR 5286, Centre Léon Bérard, Université de Lyon, Lyon, France., Marvel J; Centre International de Recherche en Infectiologie, Inserm U1111, CNRS, UMR5308, École Normale Supérieure de Lyon, Université de Lyon, Université Claude Bernard Lyon 1, Lyon, France., Bertolino P; Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR 5286, Centre Léon Bérard, Université de Lyon, Lyon, France., Aubert S; Institut de Pathologie, Centre de Biologie Pathologie, CHRU de Lille, Faculté de Médecine, Université de Lille, Lille Cedex, France., Dubus P; INSERM U1053 Bordeaux Research in Translational Oncology, University of Bordeaux, Bordeaux Cedex, France.; Plateau cellules tissus, CHU de Bordeaux, Pessac, France., Bernard D; Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR 5286, Centre Léon Bérard, Université de Lyon, Lyon, France. david.bernard@lyon.unicancer.fr.
Jazyk: angličtina
Zdroj: Cell death & disease [Cell Death Dis] 2021 Feb 16; Vol. 12 (2), pp. 190. Date of Electronic Publication: 2021 Feb 16.
DOI: 10.1038/s41419-021-03468-3
Abstrakt: Although aging is a major risk factor for most types of cancers, it is barely studied in this context. The transmembrane protein PLA2R1 (phospholipase A2 receptor) promotes cellular senescence, which can inhibit oncogene-induced tumor initiation. Functions and mechanisms of action of PLA2R1 during aging are largely unknown. In this study, we observed that old Pla2r1 knockout mice were more prone to spontaneously develop a wide spectrum of tumors compared to control littermates. Consistently, these knockout mice displayed increased Parp1, a master regulator of DNA damage repair, and decreased DNA damage, correlating with large human dataset analysis. Forced PLA2R1 expression in normal human cells decreased PARP1 expression, induced DNA damage and subsequent senescence, while the constitutive expression of PARP1 rescued cells from these PLA2R1-induced effects. Mechanistically, PARP1 expression is repressed by a ROS (reactive oxygen species)-Rb-dependent mechanism upon PLA2R1 expression. In conclusion, our results suggest that PLA2R1 suppresses aging-induced tumors by repressing PARP1, via a ROS-Rb signaling axis, and inducing DNA damage and its tumor suppressive responses.
Databáze: MEDLINE
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