Targeting the Unfolded Protein Response as a Potential Therapeutic Strategy in Renal Carcinoma Cells Exposed to Cyclosporine A.
Organ transplant patients treated with the immunosuppressive drug cyclosporine A often present malignant kidney tumors. Cyclosporine A can promote oncogenesis in a cell-intrinsic manner by increasing the production of vascular endothelial growth factor (VEGF).



We explored the impact of cyclosporine A and the role of the unfolded protein response (UPR) on three human renal cell carcinoma (RCC) cell lines under normoxic and hypoxic (1% O2) conditions.



Cyclosporine A regulated the expression of VEGF at the post-transcriptional level. Cyclosporine A induced the inositol requiring enzyme-1α (IRE1α) arm of the UPR and stabilized neosynthesized proteins in RCC cells. Toyocamycin, an inhibitor of IRE1α, abolished the clonogenic growth of RCC cells and reduced induction of VEGF by cyclosporine A under hypoxia.



Our findings highlight the impact of cyclosporine A on the proteostasis of RCC cells, and suggest the potential therapeutic interest of targeting the UPR against tumors arising in the context of organ transplantation.
Department of Pharmacology and Toxicology, Amiens University Hospital, Amiens, France.|Inserm U1088, University of Picardie Jules Verne, Amiens, France.
Sandra
S
Bodeau
Department of Biochemistry, Amiens University Hospital, Amiens, France.|EA4666, University of Picardie Jules Verne, Amiens, France.
Chloé
C
Sauzay
Department of Biochemistry, Amiens University Hospital, Amiens, France.
Rémy
R
Nyga
Department of Biochemistry, Amiens University Hospital, Amiens, France.
Christophe
C
Louandre
EA4294, University of Picardie Jules Verne, Amiens, France.
Véronique
V
Descamps
EA4294, University of Picardie Jules Verne, Amiens, France.
Catherine
C
François
Department of Biochemistry, Amiens University Hospital, Amiens, France.|EA4666, University of Picardie Jules Verne, Amiens, France.
Corinne
C
Godin
Inserm U1088, University of Picardie Jules Verne, Amiens, France.|Department of Nephrology, Amiens University Hospital, Amiens, France.
Gabriel
G
Choukroun
Department of Biochemistry, Amiens University Hospital, Amiens, France Galmiche.Antoine@chu-amiens.fr.|EA4666, University of Picardie Jules Verne, Amiens, France.
Antoine
A
Galmiche
D002292:Carcinoma, Renal Cell / Q000378:metabolism*; D045744:Cell Line, Tumor / Q000187:drug effects; D016572:Cyclosporine / Q000737:chemistry*; D004722:Endoribonucleases / Q000378:metabolism; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000860:Hypoxia; D007166:Immunosuppressive Agents / Q000737:chemistry*; D007680:Kidney Neoplasms / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011691:Puromycin / Q000737:chemistry; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D014127:Toyocamycin / Q000737:chemistry; D056811:Unfolded Protein Response; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D007166:Immunosuppressive Agents; D034741:RNA, Small Interfering; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D011691:Puromycin; D016572:Cyclosporine; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases; D014127:Toyocamycin; D010100:Oxygen
Cyclosporine A; renal cell carcinoma; toyocamycin; unfolded protein response; vascular endothelial growth factor