title: ITPR1 protects renal cancer cells against natural killer cells by inducing autophagy.
abstract: Clear cell renal cell carcinomas (RCC) frequently display inactivation of von Hippel-Lindau (VHL) gene leading to increased level of hypoxia-inducible factors (HIF). In this study, we investigated the potential role of HIF2α in regulating RCC susceptibility to natural killer (NK) cell-mediated killing. We demonstrated that the RCC cell line 786-0 with mutated VHL was resistant to NK-mediated lysis as compared with the VHL-corrected cell line (WT7). This resistance was found to require HIF2α stabilization. On the basis of global gene expression profiling and chromatin immunoprecipitation assay, we found ITPR1 (inositol 1,4,5-trisphosphate receptor, type 1) as a direct novel target of HIF2α and that targeting ITPR1 significantly increased susceptibility of 786-0 cells to NK-mediated lysis. Mechanistically, HIF2α in 786-0 cells lead to overexpression of ITPR1, which subsequently regulated the NK-mediated killing through the activation of autophagy in target cells by NK-derived signal. Interestingly, both ITPR1 and Beclin-1 silencing in 786-0 cells inhibited NK-induced autophagy and subsequently increased granzyme B activity in target cells. Finally, in vivo ITPR1 targeting significantly enhanced the NK-mediated tumor regression. Our data provide insight into the link between HIF2α, the ITPR1-related pathway, and natural immunity and strongly suggest a role for the HIF2α/ITPR1 axis in regulating RCC cell survival.
authors.affiliation: INSERM U753, Villejuif, France.
authors.forename: Yosra
authors.initials: Y
authors.lastname: Messai
authors.affiliation: INSERM U753, Villejuif, France.
authors.forename: Muhammad Zaeem
authors.initials: MZ
authors.lastname: Noman
authors.affiliation: INSERM U753, Villejuif, France.
authors.forename: Meriem
authors.initials: M
authors.lastname: Hasmim
authors.affiliation: Laboratory of Experimental Hemato-Oncology, Department of Oncology, Public Research Center for Health (CRP-Santé), L-1526 Luxembourg City, Luxembourg.
authors.forename: Bassam
authors.initials: B
authors.lastname: Janji
authors.affiliation: INSERM U753, Villejuif, France.
authors.forename: Andrés
authors.initials: A
authors.lastname: Tittarelli
authors.affiliation: INSERM U753, Villejuif, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Boutet
authors.affiliation: INSERM, U1016, Paris, France. CNRS, UMR8104, Paris, France. Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Baud
authors.affiliation: Laboratory of Experimental Hemato-Oncology, Department of Oncology, Public Research Center for Health (CRP-Santé), L-1526 Luxembourg City, Luxembourg.
authors.forename: Elodie
authors.initials: E
authors.lastname: Viry
authors.affiliation: INSERM, U1016, Paris, France. CNRS, UMR8104, Paris, France. Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Katy
authors.initials: K
authors.lastname: Billot
authors.affiliation: INSERM U753, Villejuif, France.
authors.forename: Arash
authors.initials: A
authors.lastname: Nanbakhsh
authors.affiliation: INSERM U753, Villejuif, France.
authors.forename: Thouraya
authors.initials: T
authors.lastname: Ben Safta
authors.affiliation: Functional Genomic Unit Gustave Roussy Cancer Institute, Villejuif, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Richon
authors.affiliation: Université Paris-Sud, Assistance Publique-Hôpitaux de Paris, Service d'Anatomo-Pathologie, Hôpital Bicêtre, Le Kremlin-Bicêtre France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Ferlicot
authors.affiliation: Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Donnadieu
authors.affiliation: INSERM U753, Villejuif, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Couve
authors.affiliation: INSERM U753, Villejuif, France.
authors.forename: Betty
authors.initials: B
authors.lastname: Gardie
authors.affiliation: INSERM, U1068, CRCM, Immunity and Cancer, Marseille, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Orlanducci
authors.affiliation: Medical Oncology Department, Villejuif, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Albiges
authors.affiliation: INSERM U753, Villejuif, France.
authors.forename: Jerome
authors.initials: J
authors.lastname: Thiery
authors.affiliation: INSERM, U1068, CRCM, Immunity and Cancer, Marseille, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Olive
authors.affiliation: Medical Oncology Department, Villejuif, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Escudier
authors.affiliation: INSERM U753, Villejuif, France. chouaib@gustaveroussy.fr.
authors.forename: Salem
authors.initials: S
authors.lastname: Chouaib
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D001343:Autophagy / Q000235:genetics / Q000276:immunology*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000071186:Beclin-1; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007680:Kidney Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D059467:Transcriptome; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051017:Apoptosis Regulatory Proteins; D051792:Basic Helix-Loop-Helix Proteins; D000071186:Beclin-1; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008565:Membrane Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1; C491997:BECN1 protein, human; C506926:ITPR1 protein, human