CPT2-mediated fatty acid oxidation inhibits tumorigenesis and enhances sorafenib sensitivity via the ROS/PPARγ/NF-κB pathway in clear cell renal cell carcinoma

• Published in: Cellular signalling 2023-10, Vol.110, p.110838-110838, Article 110838
• Main Authors: Zeng, Kai, Li, Qinyu, Song, Guoda, Chen, Bingliang, Luo, Min, Miao, Jianping, Liu, Bo
• Format: Article
• Language: English
• Subjects: Clear cell renal cell carcinoma; CPT2; Fatty acid oxidation; ROS; Sorafenib
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/j.cellsig.2023.110838

Kidney cancer is a common kind of tumor with approximately 400,000 new diagnoses each year. Clear cell renal cell carcinoma (ccRCC) accounts for 70–80% of all renal cell carcinomas. Lipid metabolism disorder is a hallmark of ccRCC. With a better knowledge of the importance of fatty acid oxidation (FAO) in cancer, carnitine palmitoyltransferase 2 (CPT2) has gained prominence as a major mediator in the cancer metabolic pathway. However, the biological functions and mechanism of CPT2 in the progression of ccRCC are still unclear. Herein, we performed assays in vitro and in vivo to explore CPT2 functions in ccRCC. Moreover, we discovered that CPT2 induced FAO, which inhibited the generation of reactive oxygen species (ROS) by increasing nicotinamide adenine dinucleotide phosphate (NADPH) production. Additionally, we demonstrated that CPT2 suppresses tumor proliferation, invasion, and migration by inhibiting the ROS/ PPARγ /NF-κB pathway. Gene set enrichment analysis (GSEA) and drug sensitivity analysis showed that high expression of CPT2 in ccRCC was associated with higher sorafenib sensitivity, which was also validated in vitro and in vivo. In summary, our results suggest that CPT2 acts as a tumor suppressor in the development of ccRCC through the ROS/PPARγ/NF-κB pathway. Moreover, CPT2 is a potential therapeutic target for increasing sorafenib sensitivity in ccRCC. A putative model illustrating the role of CPT2 in inhibiting tumorigenesis and enhancing sorafenib sensitivity in ccRCC: downregulation of CPT2 reduced FAO, resulting in a decrease in NADPH and an increase in ROS, which promoted ccRCC proliferation, migration, and invasion by activating the ROS/PPARγ/NF-κB pathway. [Display omitted] •CPT2 is frequently downregulated in clear cell renal cell carcinoma (ccRCC).•CPT2 induced FAO to inhibit the generation of ROS by increasing NADPH production.•CPT2 suppresses ccRCC progression by inhibiting the ROS/PPARγ/NF-κB pathway.•CPT2 is a potential therapeutic target to increase sorafenib sensitivity in ccRCC.