TY - JOUR
T1 - The autophagy sensor ITPR1 protects renal carcinoma cells from NK-mediated killing
AU - Messai, Yosra
AU - Noman, Muhammad Zaeem
AU - Janji, Bassam
AU - Hasmim, Meriem
AU - Escudier, Bernard
AU - Chouaib, Salem
N1 - Funding Information:
This work was supported by the ARTuR (Association pour la Recherche sur les Tumeurs du Rein), ARC (Association pour la Recherche sur le Cancer) 2012-2013: N SFI20121205624, La Ligue contre le Cancer and Grant from Luxembourg Institute of Health (LHCE-2013 11 05).
Funding Information:
Acknowledgments This work was supported by the ARTuR (Association pour la Recherche sur les Tumeurs du
Publisher Copyright:
© 2015, Taylor and Francis Ltd.. All rights reserved.
PY - 2015/2/25
Y1 - 2015/2/25
N2 - Clear cell renal cell carcinoma (ccRCC) is dominated by inactivating mutations in VHL (von Hippel-Lindau tumor suppressor, E3 ubiquitin protein ligase), leading to constitutive activation of the hypoxia-inducible factors (HIFs) and induction of a hypoxia response transcription signature. Our study demonstrated that VHL mutation results in the acquisition of ccRCC resistance to NK-mediated lysis by a mechanism involving EPAS1/HIF-2α stabilization. More importantly we identified ITPR1 (inositol 1,4,5-trisphosphate receptor, type 1) as a direct novel target of EPAS1 and as a potent regulator of NK-mediated killing through the activation of autophagy in target cells by a signal derived from NK cells. Therefore, it is conceivable to consider EPAS1 or the autophagy sensor ITPR1 as a potential target in future therapeutic protocols that aim to improve NK cell responses in patients with RCC and other solid malignancies.
AB - Clear cell renal cell carcinoma (ccRCC) is dominated by inactivating mutations in VHL (von Hippel-Lindau tumor suppressor, E3 ubiquitin protein ligase), leading to constitutive activation of the hypoxia-inducible factors (HIFs) and induction of a hypoxia response transcription signature. Our study demonstrated that VHL mutation results in the acquisition of ccRCC resistance to NK-mediated lysis by a mechanism involving EPAS1/HIF-2α stabilization. More importantly we identified ITPR1 (inositol 1,4,5-trisphosphate receptor, type 1) as a direct novel target of EPAS1 and as a potent regulator of NK-mediated killing through the activation of autophagy in target cells by a signal derived from NK cells. Therefore, it is conceivable to consider EPAS1 or the autophagy sensor ITPR1 as a potential target in future therapeutic protocols that aim to improve NK cell responses in patients with RCC and other solid malignancies.
KW - autophagy
KW - granzyme B
KW - hypoxia-inducible factor-2α
KW - ITPR1
KW - natural killer
KW - renal cell carcinoma
UR - http://www.scopus.com/inward/record.url?scp=85117415144&partnerID=8YFLogxK
UR - https://pubmed.ncbi.nlm.nih.gov/25714778
U2 - 10.1080/15548627.2015.1017194
DO - 10.1080/15548627.2015.1017194
M3 - Article
AN - SCOPUS:85117415144
SN - 1554-8627
VL - 2015
SP - 1
EP - 7
JO - Autophagy
JF - Autophagy
ER -