ITPR1 protects renal cancer cells against natural killer cells by inducing autophagy

Yosra Messai, Muhammad Zaeem Noman, Meriem Hasmim, Bassam Janji, Andrés Tittarelli, Marie Boutet, Éronique Baud, Elodie Viry, Katy Billot, Arash Nanbakhsh, Thouraya Ben Safta, Catherine Richon, Sophie Ferlicot, Emmanuel Donnadieu, Sophie Couve, Betty Gardie, Florence Orlucci, Laurence Albiges, Jerome Thiery, Daniel OliveBernard Escudier, Salem Chouaib*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

95 Citations (Scopus)


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 HIF2 a 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 HIF2 a stabilization. On the basis of global gene expression pro filing and chromatin immunoprecipitation assay, we found ITPR1 (inositol 1,4,5-trisphosphate receptor, type 1) as a direct novel target of HIF2a and that targeting ITPR1 significantly increased susceptibility of 786-0 cells to NK-mediated lysis. Mechanistically, HIF2a in 786-0 cells lead to overexpression of ITPR1, which subsequently regulated the NKmediated 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.

Original languageEnglish
Pages (from-to)6820-6832
Number of pages13
JournalCancer Research
Issue number23
Publication statusPublished - 1 Dec 2014


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