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

Research output: Contribution to journalArticle

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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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Peroxisome Proliferator-Activated Receptors
Dronabinol
Mixed Function Oxygenases
Gene expression
Fatty Acids
Cells
Modulation
Breast Neoplasms
Gene Expression
Up-Regulation
Palmitic Acid
Cannabis
L 663536
Protein Isoforms
Cannabinoids
Microarray Analysis
Microarrays
Oligonucleotide Array Sequence Analysis
Plasmids
Chemical activation

All Science Journal Classification (ASJC) codes

  • Toxicology

Cite this

Takeda, Shuso ; Ikeda, Eriko ; Su, Shengzhong ; Harada, Mari ; Okazaki, Hiroyuki ; Yoshioka, Yasushi ; Nishimura, Hajime ; Ishii, Hiroyuki ; Kakizoe, Kazuhiro ; Taniguchi, Aya ; Tokuyasu, Miki ; Himeno, Taichi ; Watanabe, Kazuhito ; Omiecinski, Curtis J. ; Aramaki, Hironori. / 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. In: Toxicology. 2014 ; Vol. 326. pp. 18-24.
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title = "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",
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.",
author = "Shuso Takeda and Eriko Ikeda and Shengzhong Su and Mari Harada and Hiroyuki Okazaki and Yasushi Yoshioka and Hajime Nishimura and Hiroyuki Ishii and Kazuhiro Kakizoe and Aya Taniguchi and Miki Tokuyasu and Taichi Himeno and Kazuhito Watanabe and Omiecinski, {Curtis J.} and Hironori Aramaki",
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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 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, vol. 326, pp. 18-24. https://doi.org/10.1016/j.tox.2014.09.011

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

In: Toxicology, Vol. 326, 04.12.2014, p. 18-24.

Research output: Contribution to journalArticle

TY - JOUR

T1 - δ9-THC modulation of fatty acid 2-hydroxylase (FA2H) gene expression

T2 - Possible involvement of induced levels of PPARα in MDA-MB-231 breast cancer cells

AU - Takeda, Shuso

AU - Ikeda, Eriko

AU - Su, Shengzhong

AU - Harada, Mari

AU - Okazaki, Hiroyuki

AU - Yoshioka, Yasushi

AU - Nishimura, Hajime

AU - Ishii, Hiroyuki

AU - Kakizoe, Kazuhiro

AU - Taniguchi, Aya

AU - Tokuyasu, Miki

AU - Himeno, Taichi

AU - Watanabe, Kazuhito

AU - Omiecinski, Curtis J.

AU - Aramaki, Hironori

PY - 2014/12/4

Y1 - 2014/12/4

N2 - 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.

AB - 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.

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