δ9-THC modulation of fatty acid 2-hydroxylase (FA2H) gene expression: Possible involvement of induced levels of PPARα in MDA-MB-231 breast cancer cells

Shuso Takeda, Eriko Ikeda, Shengzhong Su, Mari Harada, Hiroyuki Okazaki, Yasushi Yoshioka, Hajime Nishimura, Hiroyuki Ishii, Kazuhiro Kakizoe, Aya Taniguchi, Miki Tokuyasu, Taichi Himeno, Kazuhito Watanabe, Curtis J. Omiecinski, Hironori Aramaki

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Abstract

We recently reported that δ9-tetrahydrocannabinol (δ9-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 α (PPARα) 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 δ9-THC-treated samples and showed the selective up-regulation of the PPARα isoform coupled with the induction of FA2H over the other isoforms (β and γ). δ9-THC itself had no binding/activation potential to/on PPARα, and palmitic acid (PA), a PPARα ligand, exhibited no stimulatory effects on FA2H in MDA-MB-231 cells; thus, we hypothesized that the levels of PPARα induced were involved in the δ9-THC-mediated increase in FA2H. In support of this hypothesis, we herein demonstrated that; (i) δ9-THC activated the basal transcriptional activity of PPARα in a concentration-dependent manner, (ii) the concomitant up-regulation of PPARα/FA2H was caused by δ9-THC, (iii) PA could activate PPARα after the PPARα expression plasmid was introduced, and (iv) the δ9-THC-induced up-regulation of FA2H was further stimulated by the co-treatment with L-663,536 (a known PPARα inducer). Taken together, these results support the concept that the induced levels of PPARα may be involved in the δ9-THC up-regulation of FA2H in MDA-MB-231 cells.

Original languageEnglish (US)
Pages (from-to)18-24
Number of pages7
JournalToxicology
Volume326
DOIs
StatePublished - Dec 4 2014

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All Science Journal Classification (ASJC) codes

  • Toxicology

Cite this

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, C. J., & Aramaki, H. (2014). δ9-THC modulation of fatty acid 2-hydroxylase (FA2H) gene expression: Possible involvement of induced levels of PPARα in MDA-MB-231 breast cancer cells. Toxicology, 326, 18-24. https://doi.org/10.1016/j.tox.2014.09.011