TY - JOUR
T1 - ITPR1 protects renal cancer cells against natural killer cells by inducing autophagy
AU - Messai, Yosra
AU - Noman, Muhammad Zaeem
AU - Hasmim, Meriem
AU - Janji, Bassam
AU - Tittarelli, Andrés
AU - Boutet, Marie
AU - Baud, Éronique
AU - Viry, Elodie
AU - Billot, Katy
AU - Nanbakhsh, Arash
AU - Safta, Thouraya Ben
AU - Richon, Catherine
AU - Ferlicot, Sophie
AU - Donnadieu, Emmanuel
AU - Couve, Sophie
AU - Gardie, Betty
AU - Orlucci, Florence
AU - Albiges, Laurence
AU - Thiery, Jerome
AU - Olive, Daniel
AU - Escudier, Bernard
AU - Chouaib, Salem
N1 - Publisher Copyright:
© 2014 American Association for Cancer Research.
PY - 2014/12/1
Y1 - 2014/12/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/84917705638
U2 - 10.1158/0008-5472.CAN-14-0303
DO - 10.1158/0008-5472.CAN-14-0303
M3 - Article
C2 - 25297632
AN - SCOPUS:84917705638
SN - 0008-5472
VL - 74
SP - 6820
EP - 6832
JO - Cancer Research
JF - Cancer Research
IS - 23
ER -