Δ9-Tetrahydrocannabinol upregulates fatty acid 2-hydroxylase (FA2H) via PPARα induction: A possible evidence for the cancellation of PPARβ/δ-mediated inhibition of PPARα in MDA-MB-231 cells

Peroxisome proliferator-activated receptors (PPARs) are a family of ligand-activated nuclear transcription factors, with three characterized subtypes: PPARα, PPARβ/δ, and PPARγ. The biological correlation between the two PPAR subtypes PPARα and γ and carcinogenesis is well-characterized; however, substantially less is known about the biological functions of PPARβ/δ. PPARβ/δ has been reported to repress transcription when PPARβ/δ and PPARα or PPARγ are simultaneously expressed in some cells, and MDA-MB-231 cells express functional levels of PPARβ/δ. We have previously reported that Δ⁹-tetrahydrocannabinol (Δ⁹-THC), a major cannabinoid component of the drug-type cannabis plant, can stimulate the expression of fatty acid 2-hydroxylase (FA2H) via upregulation of PPARα expression in human breast cancer MDA-MB-231 cells. Although the possibility of an inhibitory interaction between PPARα and PPARβ/δ has not been demonstrated in MDA-MB-231 cells, we reasoned if this interaction were to exist, Δ⁹-THC should make PPARα free to achieve FA2H induction. Here, we show that a PPARβ/δ-mediated suppression of PPARα function, but not of PPARγ, exists in MDA-MB-231 cells and Δ⁹-THC causes FA2H induction via mechanisms underlying the cancellation of PPARβ/δ-mediated inhibition of PPARα, in addition to the upregulation of PPARα.