The convergent roles of NF-κB and ER stress in sunitinib-mediated expression of pro-tumorigenic cytokines and refractory phenotype in renal cell carcinoma

Peter Makhov*, Sei Naito, Miki Haifler, Alexander Kutikov, Yanis Boumber, Robert G. Uzzo, Vladimir M. Kolenko

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

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-α, and a TRAF2-mediated NF-κB survival program that protects tumor cells against cell death. PERK blockade completely prevents sunitinib-induced expression of IL-6, IL-8 and TNF-α, whereas NF-κB 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.

Original languageEnglish (US)
Article number374
JournalCell Death and Disease
Volume9
Issue number3
DOIs
StatePublished - Mar 1 2018
Externally publishedYes

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

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