title: 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.
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.
authors.affiliation: Department of Molecular Biology, Daiichi University of Pharmacy, 22-1 Tamagawa-cho, Minami-ku, Fukuoka 815-8511, Japan; Laboratory of Xenobiotic Metabolism and Environmental Toxicology, Faculty of Pharmaceutical Sciences, Hiroshima International University (HIU), 5-1-1 Hiro-koshingai, Kure, Hiroshima 737-0112, Japan.
authors.forename: Shuso
authors.initials: S
authors.lastname: Takeda
authors.affiliation: Department of Molecular Biology, Daiichi University of Pharmacy, 22-1 Tamagawa-cho, Minami-ku, Fukuoka 815-8511, Japan.
authors.forename: Eriko
authors.initials: E
authors.lastname: Ikeda
authors.affiliation: Center for Molecular Toxicology and Carcinogenesis, 101 Life Sciences Building, Pennsylvania State University, University Park, PA 16802, United States.
authors.forename: Shengzhong
authors.initials: S
authors.lastname: Su
authors.affiliation: Department of Molecular Biology, Daiichi University of Pharmacy, 22-1 Tamagawa-cho, Minami-ku, Fukuoka 815-8511, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Harada
authors.affiliation: Drug Innovation Research Center, Daiichi University of Pharmacy, 22-1 Tamagawa-cho, Minami-ku, Fukuoka 815-8511, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Okazaki
authors.affiliation: Department of Molecular Biology, Daiichi University of Pharmacy, 22-1 Tamagawa-cho, Minami-ku, Fukuoka 815-8511, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yoshioka
authors.affiliation: Department of Molecular Biology, Daiichi University of Pharmacy, 22-1 Tamagawa-cho, Minami-ku, Fukuoka 815-8511, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Nishimura
authors.affiliation: Department of Molecular Biology, Daiichi University of Pharmacy, 22-1 Tamagawa-cho, Minami-ku, Fukuoka 815-8511, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ishii
authors.affiliation: Department of Molecular Biology, Daiichi University of Pharmacy, 22-1 Tamagawa-cho, Minami-ku, Fukuoka 815-8511, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kakizoe
authors.affiliation: Department of Molecular Biology, Daiichi University of Pharmacy, 22-1 Tamagawa-cho, Minami-ku, Fukuoka 815-8511, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Taniguchi
authors.affiliation: Department of Molecular Biology, Daiichi University of Pharmacy, 22-1 Tamagawa-cho, Minami-ku, Fukuoka 815-8511, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Tokuyasu
authors.affiliation: Department of Molecular Biology, Daiichi University of Pharmacy, 22-1 Tamagawa-cho, Minami-ku, Fukuoka 815-8511, Japan.
authors.forename: Taichi
authors.initials: T
authors.lastname: Himeno
authors.affiliation: Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku University, Ho-3 Kanagawa-machi, Kanazawa 920-1181, Japan.
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Watanabe
authors.affiliation: Center for Molecular Toxicology and Carcinogenesis, 101 Life Sciences Building, Pennsylvania State University, University Park, PA 16802, United States.
authors.forename: Curtis J
authors.initials: CJ
authors.lastname: Omiecinski
authors.affiliation: Department of Molecular Biology, Daiichi University of Pharmacy, 22-1 Tamagawa-cho, Minami-ku, Fukuoka 815-8511, Japan; Drug Innovation Research Center, Daiichi University of Pharmacy, 22-1 Tamagawa-cho, Minami-ku, Fukuoka 815-8511, Japan. Electronic address: haramaki@daiichi-cps.ac.jp.
authors.forename: Hironori
authors.initials: H
authors.lastname: Aramaki
mesh_terms: D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics; D045744:Cell Line, Tumor; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000494:pharmacology*; D004790:Enzyme Induction; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D006899:Mixed Function Oxygenases / Q000096:biosynthesis* / Q000235:genetics; D047493:PPAR alpha / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D015854:Up-Regulation; D002722:Chlorobenzenes
chemical_list: D019363:Cytochrome P-450 CYP1A1; D013759:Dronabinol; D007211:Indoles; D006899:Mixed Function Oxygenases; D047493:PPAR alpha; C060893:MK-886; D002722:Chlorobenzenes; C019081:fatty acid alpha-hydroxylase; C569463:CYP1A1 protein, human
keywords: Fatty acid 2-hydroxylase; Human breast cancer cells; MDA-MB-231 cells; Peroxisome proliferator-activated receptorα; Δ(9)-tetrahydrocannabinol