title: PLA2R1 mediates tumor suppression by activating JAK2.
abstract: Little is known about the physiological role of the phospholipase A2 receptor (PLA2R1). PLA2R1 has been described as regulating the replicative senescence, a telomerase-dependent proliferation arrest. The downstream PLA2R1 signaling and its role in cancer are currently unknown. Senescence induction in response to activated oncogenes is a failsafe program of tumor suppression that must be bypassed for tumorigenesis. We now present evidence that PLA2R1 functions in vitro as a tumor suppressor, the depletion of which is sufficient to escape oncogene-induced senescence (OIS), thereby facilitating oncogenic cell transformation. Furthermore, mice that are genetically deficient in PLA2R1 display increased sensitivity to RAS-induced tumorigenesis by facilitating OIS escape, highlighting its physiological role as a tumor suppressor. Unexpectedly, PLA2R1 activated JAK2 and its effector signaling, with PLA2R1-mediated inhibition of cell transformation largely reverted in JAK2-depleted cells. This finding was unexpected as the JAK2 pathway has been associated mainly with protumoral functions and several inhibitors are currently in clinical trials. Taken together, our findings uncover an unanticipated tumor suppressive role for PLA2R1 that is mediated by targeting downstream JAK2 effector signaling.
authors.affiliation: Authors' Affiliations: Inserm U1052, Centre de Recherche en Cancérologie de Lyon; CNRS UMR5286; Centre Léon Bérard; Université de Lyon, Lyon; UMR8161, CNRS/Universités de Lille 1 et 2; Institut de Pharmacologie Moléculaire et Cellulaire, UMR7275, CNRS and Université de Nice-Sophia Antipolis, Valbonne; INSERM U916, Bergonié Cancer Institute, Université Bordeaux, Bordeaux; and Institut de Pathologie, CHRU, Faculté de Médecine, Université de Lille; INSERM U837, Jean-Pierre Aubert Research Center, Team 5, Lille; Department of Medicine, University of Washington, Seattle, Washington.
authors.forename: David
authors.initials: D
authors.lastname: Vindrieux
authors.forename: Arnaud
authors.initials: A
authors.lastname: Augert
authors.forename: Christophe A
authors.initials: CA
authors.lastname: Girard
authors.forename: Delphine
authors.initials: D
authors.lastname: Gitenay
authors.forename: Helene
authors.initials: H
authors.lastname: Lallet-Daher
authors.forename: Clotilde
authors.initials: C
authors.lastname: Wiel
authors.forename: Benjamin
authors.initials: B
authors.lastname: Le Calvé
authors.forename: Baptiste
authors.initials: B
authors.lastname: Gras
authors.forename: Mylène
authors.initials: M
authors.lastname: Ferrand
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Verbeke
authors.forename: Yvan
authors.initials: Y
authors.lastname: de Launoit
authors.forename: Xavier
authors.initials: X
authors.lastname: Leroy
authors.forename: Alain
authors.initials: A
authors.lastname: Puisieux
authors.forename: Sébastien
authors.initials: S
authors.lastname: Aubert
authors.forename: Michael
authors.initials: M
authors.lastname: Perrais
authors.forename: Michael
authors.initials: M
authors.lastname: Gelb
authors.forename: Hélène
authors.initials: H
authors.lastname: Simonnet
authors.forename: Gérard
authors.initials: G
authors.lastname: Lambeau
authors.forename: David
authors.initials: D
authors.lastname: Bernard
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques; D048708:Cell Growth Processes / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D016922:Cellular Senescence / Q000235:genetics / Q000502:physiology; D004789:Enzyme Activation; D006801:Humans; D007150:Immunohistochemistry; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D041681:NIH 3T3 Cells; D054507:Receptors, Phospholipase A2 / Q000235:genetics / Q000378:metabolism*; D012878:Skin Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D014162:Transfection
chemical_list: C516360:PLA2R1 protein, human; C516357:Pla2r1 protein, mouse; D054507:Receptors, Phospholipase A2; D053614:Janus Kinase 2