Curcumin restores sensitivity to retinoic acid in triple negative breast cancer cells

Background: A major obstacle in the use of retinoid therapy in cancer is the resistance to this agent in tumors. Retinoic acid facilitates the growth of mammary carcinoma cells which express high levels of fatty acid-binding protein 5 (FABP5). This protein delivers retinoic acid to peroxisome proliferator-activated receptor beta/delta (PPAR beta/delta) that targets genes involved in cell proliferation and survival. One approach to overcome resistance of mammary carcinoma cells to retinoic acid is to target and suppress the FABP5/PPAR beta/delta pathway. The objective of this research was to investigate the effect of curcumin, a polyphenol extract from the plant Curcuma longa, on the FABP5/PPAR beta/delta pathway in retinoic acid resistant triple negative breast cancer cells. Methods: Cell viability and proliferation of triple negative breast cancer cell lines (MDA-MB-231 and MD-MB-468) treated with curcumin and/or retinoic was analyzed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and 5-bromo-2'-deoxyuridine (BrdU). Expression level of FABP5 and PPAR beta/delta in these cells treated with curcumin was examined by Western Blotting analysis and Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR). Effect of curcumin and retinoic acid on PPAR beta/delta target genes, PDK1and VEGF-A were also examined using qRT-PCR. Western Blotting was utilized to examine the protein expression level of the p65 subunit of NF-kappa B. Results: Treatment of retinoic acid resistant triple negative breast cancer cells with curcumin sensitized these cells to retinoic acid mediated growth suppression, as well as suppressed incorporation of BrdU. Further studies demonstrated that curcumin showed a marked reduction in the expression level of FABP5 and PPAR beta/delta. We provide evidence that curcumin suppresses p65, a transcription factor known to regulate FABP5. The combination of curcumin with retinoic acid suppressed PPAR beta/delta target genes, VEGF-A and PDK1. Conclusions: Curcumin suppresses the expression level of FABP5 and PPAR beta/delta in triple negative mammary carcinoma cells. By targeting the FABP5/PPAR beta/delta pathway, curcumin prevents the delivery of retinoic acid to PPAR beta/delta and suppresses retinoic acid-induced PPAR beta/delta target gene, VEGF-A. Our data demonstrates that suppression of the FABP5/PPAR beta/delta pathway by curcumin sensitizes retinoic acid resistant triple negative breast cancer cells to retinoic acid mediated growth suppression.