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 (PPARα),
androgen receptor (AR) and PPARγ, were significantly increased in
sunitinib-treated samples compared with control samples. RT-PCR analysis showed that the PPARα expression at the
mRNA level was significantly increased in
sunitinib-resistant A498, CaKi-1 and 780-O ccRCC lines compared with their
sunitinib-sensitive parental cells. Furthermore, knockdown of PPARα 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-κB) signaling pathway was activated in
sunitinib-resistant ccRCC lines, indicating that PPARα and NF-κB inhibition could play a synergistic role to modulate
sunitinib resistance and suggesting that PPARα could be used as a potential target to overcome
sunitinib resistance via the NF-κB pathway.