Δ(9)-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. 2014 Dec 4;326:18-24. doi: 10.1016/j.tox.2014.09.011. Epub 2014 Oct 5.

Abstract

We recently reported that Δ(9)-tetrahydrocannabinol (Δ(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 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 Δ(9)-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). Δ(9)-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 Δ(9)-THC-mediated increase in FA2H. In support of this hypothesis, we herein demonstrated that; (i) Δ(9)-THC activated the basal transcriptional activity of PPARα in a concentration-dependent manner, (ii) the concomitant up-regulation of PPARα/FA2H was caused by Δ(9)-THC, (iii) PA could activate PPARα after the PPARα expression plasmid was introduced, and (iv) the Δ(9)-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 Δ(9)-THC up-regulation of FA2H in MDA-MB-231 cells.

Keywords: Fatty acid 2-hydroxylase; Human breast cancer cells; MDA-MB-231 cells; Peroxisome proliferator-activated receptorα; Δ(9)-tetrahydrocannabinol.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / enzymology*
  • Breast Neoplasms / genetics
  • Cell Line, Tumor
  • Cytochrome P-450 CYP1A1 / biosynthesis
  • Cytochrome P-450 CYP1A1 / genetics
  • Dose-Response Relationship, Drug
  • Dronabinol / pharmacology*
  • Enzyme Induction
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Indoles / pharmacology
  • Mixed Function Oxygenases / biosynthesis*
  • Mixed Function Oxygenases / genetics
  • PPAR alpha / drug effects*
  • PPAR alpha / genetics
  • PPAR alpha / metabolism
  • Signal Transduction / drug effects*
  • Time Factors
  • Transcription, Genetic
  • Transfection
  • Up-Regulation

Substances

  • Indoles
  • PPAR alpha
  • MK-886
  • Dronabinol
  • Mixed Function Oxygenases
  • fatty acid alpha-hydroxylase
  • CYP1A1 protein, human
  • Cytochrome P-450 CYP1A1