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PPAR? mediates sunitinib resistance via NF-?B activation in clear cell renal cell carcinoma.

ABSTRACT: 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?), androgen receptor (AR) and PPAR?, were significantly increased in sunitinib-treated samples compared with control samples. RT-PCR analysis showed that the PPAR? 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 PPAR? 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-?B) signaling pathway was activated in sunitinib-resistant ccRCC lines, indicating that PPAR? and NF-?B inhibition could play a synergistic role to modulate sunitinib resistance and suggesting that PPAR? could be used as a potential target to overcome sunitinib resistance via the NF-?B pathway.

SUBMITTER: Aimudula A

PROVIDER: S-EPMC6958248 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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

Aimudula Ainiwaer A Nasier Huerxidan H Yang Ying Y Zhang Ruili R Lu Pengfei P Hao Jie J Bao Yongxing Y

International journal of clinical and experimental pathology 20180501 5

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 o ...[more]

PMID: 31938351

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Project description:BackgroundClear cell renal cell carcinoma (ccRCC) is one of the most prevalent malignant diseases in the urinary system with more than 140,000 related deaths annually. Ubiquitination-deubiquitination homeostasis is an important factor in ccRCC progression; ubiquitin-specific peptidase 53 (USP53) belongs to the family of deubiquitinating enzymes, but its functions are rarely reported.MethodsDatabases obtained from GEO and TCGA were analyzed to reveal the role of USP53 in ccRCC. CCK-8/BrdU and EDU assays were used to detect the proliferation of ccRCC after USP53 overexpression or knockdown. A tumor xenograft experiment was used to verify the effect of the proliferation of ccRCC after USP53 knockdown. Transwell assays were used to detect the metastasis of ccRCC after USP53 overexpression or knockdown. RNA sequencing and western blot analysis were employed to detect the change in genes after USP53 overexpression and knockdown. Then we tested the effect of USP53 on IκBα protein stability through western blot analysis. Detect the effect of USP53 on IκBα ubiquitination in vitro by immunoprecipitation method.ResultsUSP53 expression was downregulated in ccRCC tissues and USP53 expression was significantly negatively correlated with the tumor progression and clinical prognosis. The ability of growth and metastasis of ccRCC was inhibited after USP53 overexpression. In addition, USP53 knockdown promoted ccRCC growth and metastasis. Moreover, USP53 knockdown promoted the ability of clone formation of ccRCC in vivo. NF-κB signaling pathway significantly enriched and downregulated in USP53 overexpressed cells, and genes in the NF-κB pathway (such as IL1B, CXCL1-3, RELA, RELB, etc.) were obviously downregulated in USP53 overexpressed cells. USP53 overexpression decreased the phosphorylation of IKKβ and P65 in both Caki-1 and 786-O cells, and the expression of IκBα was increased. Phosphorylation of IKKβ and P65 was increased in both Caki-1 and 786-O cells after USP53 knockdown. As the expression of USP53 increases, the protein expression of IκBα was also gradually increased and USP53 reduced the ubiquitination of IκBα.ConclusionIn summary, our data indicate that USP53 inhibits the inactivation of the NF-κB pathway by reducing the ubiquitination of IκBα to further inhibit ccRCC proliferation and metastasis. These findings may help understand the pathogenesis of ccRCC and introduce new potential therapeutic targets for kidney cancer patients.

Dataset Information

PPAR? mediates sunitinib resistance via NF-?B activation in clear cell renal cell carcinoma.

Publications

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

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