Delta(9)-THC modulation of fatty acid 2-hydroxylase (FA2H) gene expression: possible involvement of induced levels of PPARalpha in MDA-MB-231 breast cancer cells.
Article Details
- CitationCopy to clipboard
Takeda S, Ikeda E, Su S, Harada M, Okazaki H, Yoshioka Y, Nishimura H, Ishii H, Kakizoe K, Taniguchi A, Tokuyasu M, Himeno T, Watanabe K, Omiecinski CJ, Aramaki H
Delta(9)-THC modulation of fatty acid 2-hydroxylase (FA2H) gene expression: possible involvement of induced levels of PPARalpha in MDA-MB-231 breast cancer cells.
Toxicology. 2014 Dec 4;326:18-24. doi: 10.1016/j.tox.2014.09.011. Epub 2014 Oct 5.
- PubMed ID
- 25291031 [ View in PubMed]
- Abstract
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 (PPARalpha) 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 PPARalpha 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 PPARalpha, and palmitic acid (PA), a PPARalpha ligand, exhibited no stimulatory effects on FA2H in MDA-MB-231 cells; thus, we hypothesized that the levels of PPARalpha 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 PPARalpha in a concentration-dependent manner, (ii) the concomitant up-regulation of PPARalpha/FA2H was caused by Delta(9)-THC, (iii) PA could activate PPARalpha after the PPARalpha 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 PPARalpha inducer). Taken together, these results support the concept that the induced levels of PPARalpha may be involved in the Delta(9)-THC up-regulation of FA2H in MDA-MB-231 cells.