Abstract 1389: Obesity paradox on ccRCC: A role of fatty acids?

Abstract Introduction: Obesity is a risk factor for clear cell renal cell carcinoma (ccRCC), the most common type of kidney cancer; coincidentally obesity correlates with better outcomes in ccRCC patients, a phenomenon known as the obesity paradox. Obesity is frequently associated with the consumption of diets enriched in lipids. However, how dietary composition, especially the role of different fatty acids (FAs), can affect ccRCC development, as well as how dietary modification could be used in combination with other therapies for better responses is still unclear. We hypothesize that obese individuals with ccRCC respond better to the therapies due to increased amounts of specific FAs in the circulation, which somehow can sensibilize the tumor cells. Methods: We used two ccRCC cell lines, UOK101 and 786-O, and a proximal tubular cell line derived from normal kidney, HK-2, as a control. Palmitic acid (PA), oleic acid (OA), and linoleic acid (LA), which are saturated, monounsaturated, and polyunsaturated FAs, respectively, were used as stimuli for the cells, mimicking the levels of FAs found in circulation of individuals with obesity [200 µM]. Lipid droplets (LDs) were evaluated by Oil Red O staining; Viability by MTT; Protein expression by Western Blotting; Oxygen Consumption rate (OCR) by Seahorse; Survival by clonogenic assay; mRNA by RT-qPCR, Cell death by Annexin-V/PI kit; ROS by DCFDA/H2DCFDA kit; Mitochondrial potential by MitoTracker®, Gene expression profile by RNAseq. Results: All FAs increased the amount of LDs compared to the control, but PA was the least potent. PA impaired the growth rate for the tumor cells compared to the control from 24h, which remained in 72h, even at the lowest concentration [50 uM]. LA also decreased the growth rate, but only at 72h. PA, even at a lower concentration, impaired the formation of colonies for both cell lines compared to control and other FAs. LA impaired colony formation only at the higher concentration. PA also decreased cells migration at the time of 12h, induced cell death and increased cleaved caspase3 expression in 24h, a phenomenon observed only for the tumor cell lines. Regarding lipid metabolism, all FAs decreased fatty acid synthase and increased CPT1 expression, suggesting increase in fatty acid oxidation (FAO). In contrast all FAs decreased OCR, and blocking FAO did not rescue cell death induced by PA. PA decreased mitochondrial membrane potential and also DRP1 protein for UOK, although cytochrome C expression or either ROS production were not increased. Gene expression profiling indicated that PA induces endoplasmic reticulum stress. Conclusion: In summary, we demonstrated that PA decreased malignant characteristics in ccRCC, such as viability, colony formation, migration, and induced cell death. Taken together, our data suggest that PA could be employed as an intervention in ccRCC treatment, although additional studies are required to evaluate how an enriched PA-high fat diet can impart a better outcome for patients. Citation Format: Isadora Ramos de Andrade. Obesity paradox on ccRCC: A role of fatty acids? [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1389.