Laboratory of Xenobiotic Metabolism and Environmental Toxicology, Faculty of Pharmaceutical Sciences, Hiroshima International University, 5-1-1 Hiro-koshingai, Kure, Hiroshima, 737-0112, Japan.
Department of Hygienic Chemistry, Daiichi University of Pharmacy, 22-1 Tamagawa-cho, Minami-ku, Fukuoka, 815-8511, Japan.
Arch Biochem Biophys. 2022 Nov 30;731:109428. doi: 10.1016/j.abb.2022.109428. Epub 2022 Oct 10.
Cannabidiolic acid (CBDA) can activate peroxisome proliferator-activated receptor-α (PPARα) and PPARγ. Whether CBDA can activate PPARβ/δ has not been examined sufficiently to date. Since previous studies showed that triple-negative breast cancer cells respond to activation of PPARβ/δ, the present study examined the effect of CBDA in MDA-MB-231 cells and compared the activities of CBDA with known PPARβ/δ agonists/antagonists. Expression of the PPARβ/δ target genes angiopoietin-like 4 (ANGPTL4) and adipocyte differentiation-related protein (ADRP) was increased by CBDA. Interestingly, ligand activation of PPARβ/δ with GW501516 caused an increase in expression of both ANGPTL4 and ADRP, but the magnitude of this effect was markedly increased when co-treated with CBDA. Specificity of these effects were confirmed by showing that CBDA-induced expression of ANGPTL4 and ADRP is mitigated in the presence of either a PPARβ/δ antagonist or an inverse agonist. Results from these studies suggest that CBDA can synergize with PPARβ/δ and might interact with endogenous agonists that modulate PPARβ/δ function.
大麻二酚酸 (CBDA) 可以激活过氧化物酶体增殖物激活受体-α (PPARα) 和 PPARγ。迄今为止，尚未充分研究 CBDA 是否可以激活 PPARβ/δ。由于先前的研究表明，三阴性乳腺癌细胞对 PPARβ/δ 的激活有反应，因此本研究检查了 CBDA 在 MDA-MB-231 细胞中的作用，并比较了 CBDA 与已知的 PPARβ/δ 激动剂/拮抗剂的活性。CBDA 增加了 PPARβ/δ 靶基因血管生成素样 4 (ANGPTL4) 和脂肪细胞分化相关蛋白 (ADRP) 的表达。有趣的是，PPARβ/δ 的配体 GW501516 的激活导致 ANGPTL4 和 ADRP 的表达均增加，但当与 CBDA 共同处理时，这种作用的幅度显着增加。通过显示在存在 PPARβ/δ 拮抗剂或反向激动剂的情况下，CBDA 诱导的 ANGPTL4 和 ADRP 表达被减轻，证实了这些作用的特异性。这些研究结果表明，CBDA 可以与 PPARβ/δ 协同作用，并可能与调节 PPARβ/δ 功能的内源性激动剂相互作用。
