Delta 9-THC modulation of fatty acid 2-hydroxylase (FA2H) gene expression: Possible involvement of induced levels of PPAR alpha in MDA-MB-231 breast cancer cells

We recently reported that Delta 9-tetrahydrocannabinol ( Delta 9-THC), a major cannabinoid component in Cannabis Sativa (marijuana), significantly stimulated the expression of fatty acid 2-hydroxylase (FA2H) in human breast cancer MDA-MB-231 cells. Peroxisome proliferator-activated receptor alpha (PPAR alpha ) was previously implicated in this induction. However, the mechanisms mediating this induction have not been elucidated in detail. We performed a DNA microarray analysis of Delta 9-THC-treated samples and showed the selective up-regulation of the PPAR alpha isoform coupled with the induction of FA2H over the other isoforms ( beta and gamma ). Delta 9-THC itself had no binding/activation potential to/on PPAR alpha , and palmitic acid (PA), a PPAR alpha ligand, exhibited no stimulatory effects on FA2H in MDA-MB-231 cells; thus, we hypothesized that the levels of PPAR alpha induced were involved in the Delta 9-THC-mediated increase in FA2H. In support of this hypothesis, we herein demonstrated that; (i) Delta 9-THC activated the basal transcriptional activity of PPAR alpha in a concentration-dependent manner, (ii) the concomitant up-regulation of PPAR alpha /FA2H was caused by Delta 9-THC, (iii) PA could activate PPAR alpha after the PPAR alpha expression plasmid was introduced, and (iv) the Delta 9-THC-induced up-regulation of FA2H was further stimulated by the co-treatment with L-663,536 (a known PPAR alpha inducer). Taken together, these results support the concept that the induced levels of PPAR alpha may be involved in the Delta 9-THC up-regulation of FA2H in MDA-MB-231 cells.