PPARα mediates sunitinib resistance via NF-κB activation in clear cell renal cell carcinoma

Sunitinib is used as standard treatment for metastatic or unresectable clear cell renal cell carcinoma (ccRCC). However, ccRCC eventually develops resistance to sunitinib in most cases, and the mechanisms underlying such resistance have not been fully determined. Nuclear receptors (NRs) are a class of transcription factors that regulate many cellular functions by controlling gene expression, and they also play important roles in tumor development, proliferation and progression in various types of cancers. In the present study, we aimed to explore the mechanisms underlying sunitinib resistance in RCC and the potential role of NRs in sunitinib resistance. The expression profile of NRs was obtained from the Gene Expression Omnibus (GEO) RNAseq database. A total of 138 patients from GSE65615 were examined in this study. From the GEO metadata, we found that the expressions of three genes, encoding peroxisome proliferator activated receptor alpha (PPAR alpha), androgen receptor (AR) and PPAR gamma, were significantly increased in sunitinib-treated samples compared with control samples. RT-PCR analysis showed that the PPAR alpha expression at the mRNA level was significantly increased in sunitinib-resistant A498, CaKi-1 and 780-0 ccRCC lines compared with their sunitinib-sensitive parental cells. Furthermore, knockdown of PPAR alpha significantly inhibited cell proliferation in all three sunitinib-resistant ccRCC lines, successfully overcoming the resistance to sunitinib. Our results also showed that nuclear factor kappa B (NF-kappa B) signaling pathway was activated in sunitinib-resistant ccRCC lines, indicating that PPAR alpha and NF-kappa B inhibition could play a synergistic role to modulate sunitinib resistance and suggesting that PPAR alpha could be used as a potential target to overcome sunitinib resistance via the NF-kappa B pathway.