WY-14643 attenuates lipid deposition via activation of the PPARα/CPT1A axis by targeting Gly335 to inhibit cell proliferation and migration in ccRCC

Abstract

Background Histologically, cytoplasmic deposits of lipids and glycogen are common in clear cell renal cell carcinoma (ccRCC). Owing to the significance of lipid deposition in ccRCC, numerous trials targeting lipid metabolism have shown certain therapeutic potential. The agonism of peroxisome proliferator-activated receptor-α (PPARα) via ligands, including WY-14,643, has been considered a promising intervention for cancers. Methods First, the effects of WY-14,643 on malignant behaviors were investigated in ccRCC in vitro. After RNA sequencing, the changes in lipid metabolism, especially neutral lipids and glycerol, were further evaluated. Finally, the underlying mechanisms were revealed. Results Phenotypically, the proliferation and migration of ccRCC cells treated with WY-14,643 were significantly inhibited in vitro. A theoretical functional mechanism was proposed in ccRCC: WY-14,643 mediates lipid consumption by recognizing carnitine palmitoyltransferase 1 A (CPT1A). Activation of PPARα using WY-14,643 reduces lipid deposition by increasing the CPT1A level, which also suppresses the NF-κB signaling pathway. Spatially, WY-14,643 binds and activates PPARα by targeting Gly335. Conclusion Overall, WY-14,643 suppresses the biological behaviors of ccRCC in terms of cell proliferation, migration, and cell cycle arrest. Furthermore, its anticancer properties are mediated by the inhibition of lipid accumulation, at least in part, through the PPARα/CPT1A axis by targeting Gly335, as part of the process, NF-κB signaling is also suppressed. Pharmacological activation of PPARα might offer a new treatment option for ccRCC.

Novel Effect of p-Coumaric Acid on Hepatic Lipolysis: Inhibition of Hepatic Lipid-Droplets

“…At both the mRNA and protein levels, p -CA increased the expression of PPARγ ( Figure 6 A,B). To study its importance regarding the hypolipidemic effects of p -CA, a selective antagonist of PPARγ, GW9662 [ 32 ], was used in vitro. In control groups, p -CA reduced the TG content in the Triton WR1339-induced lipid overloading model.…”

Deficiency of SDHC promotes metastasis by reprogramming fatty acid metabolism in colorectal cancer

“…PTPRO could suppress CRC development and metastasis by modulating the MAPK/PPARα/ACOX1 pathways and reprogramming lipid metabolism 27 . Activating the PPARα/CPT1A axis alleviates lipid accumulation and inhibits cell proliferation and migration of clear cell renal cell carcinoma 35 . The miR-532-5p could drives nodal metastasis of cervical cancer through CPT1A-mediated lipid droplet accumulation 24 .…”