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

  • Tumor Immunotherapy and Microenvironment
December 01, 2014 By:
  • Messai Y
  • Noman MZ
  • Hasmim M
  • Janji B
  • Tittarelli A
  • Boutet M
  • Baud V
  • Viry E
  • Billot K
  • Nanbakhsh A
  • Ben Safta T
  • Richon C
  • Ferlicot S
  • Donnadieu E
  • Couve S
  • Gardie B
  • Orlanducci F
  • Albiges L
  • Thiery J
  • Olive D
  • Escudier B
  • Chouaib S.

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 HIF2alpha 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 HIF2alpha 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 HIF2alpha and that targeting ITPR1 significantly increased susceptibility of 786-0 cells to NK-mediated lysis. Mechanistically, HIF2alpha 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 HIF2alpha, the ITPR1-related pathway, and natural immunity and strongly suggest a role for the HIF2alpha/ITPR1 axis in regulating RCC cell survival.

2014 Dec. Cancer Res.74(23):6820-32. Epub 2014 Oct 8.
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