Journal
ANTICANCER RESEARCH
Volume 37, Issue 3, Pages 1049-1057Publisher
INT INST ANTICANCER RESEARCH
DOI: 10.21873/anticanres.11416
Keywords
Cyclosporine A; renal cell carcinoma; unfolded protein response; vascular endothelial growth factor; toyocamycin
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Funding
- Association Santelys
- Ligue contre le Cancer, comite de la Somme
- CHU Amiens
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Background/Aim: 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). Materials and Methods: 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% O-2) conditions. Resullt:Cyclosporine A regulated the expression of VEGF at the post-transcriptional level. Cyclosporine A induced the inositol requiring enzyme-1 alpha (IRE1 alpha) arm of the UPR and stabilized neosynthesized proteins in RCC cells. Toyocamycin, an inhibitor of IRE1 alpha, abolished the clonogenic growth of RCC cells and reduced induction of VEGF by cyclosporine A under hypoxia. Conclusion: 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.
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