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The convergent roles of NF-kappaB and ER stress in sunitinib-mediated expression of pro-tumorigenic cytokines and refractory phenotype in renal cell carcinoma
Cell Death Dis. 2018 Mar 7;9(3) :374
PMID: 29515108    PMCID: PMC5841329   
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Renal cell carcinoma (RCC) is the most common form of kidney cancer. While cure remains exceptionally infrequent in RCC patients with systemic or recurrent disease, current targeted molecular strategies, including multi-targeted tyrosine kinase inhibitors (TKIs), notably changed the treatment paradigm of advanced renal cancer. Yet, complete and durable responses have been noted in only a few cases. Our studies reveal that sunitinib triggers two resistance-promoting signaling pathways in RCC cells, which emanate from the endoplasmic reticulum (ER) stress response: a PERK-driven ER stress response that induces expression of the pro-tumorigenic cytokines IL-6, IL-8, and TNF-alpha, and a TRAF2-mediated NF-kappaB survival program that protects tumor cells against cell death. PERK blockade completely prevents sunitinib-induced expression of IL-6, IL-8 and TNF-alpha, whereas NF-kappaB inhibition reinstates sensitivity of RCC cells to sunitinib both in vitro and in vivo. Taken together, our findings indicate that ER stress response may contribute to sunitinib resistance in RCC patients.
2041-4889 Makhov, Peter Naito, Sei Haifler, Miki Kutikov, Alexander Boumber, Yanis Uzzo, Robert G Kolenko, Vladimir M Journal Article England Cell Death Dis. 2018 Mar 7;9(3):374. doi: 10.1038/s41419-018-0388-1.