Δ⁹-Tetrahydrocannabinol Targeting Estrogen Receptor Signaling: The Possible Mechanism of Action Coupled with Endocrine Disruption

Abstract

Δ9 -Tetrahydrocannabinol (Δ 9 -THC), a biologically active constituent of marijuana, possesses a wide variety of pharmacological and toxicological effects (e.g., analgesia, hypotension, reduction of inflammation, and anti-cancer effects). Among Δ 9 -THC's biological activities, its recognized anti-estrogenic activity has been the subject of investigations. Since Δ 9 -THC is used as both a drug of abuse (marijuana) and as a preventive therapeutic to treat pain and nausea in cancer patients undergoing chemotherapy in the United States and other countries (synthesized Δ 9 -THC; dronabinol), it is important to investigate the mechanistic basis underlying the anti-estrogenic activity of Δ 9 -THC. Since Δ 9 -THC has "no" binding potential for estrogen receptor α (ERα) which can be activated by estrogen (E2), the question of how Δ 9 -THC exerts its inhibitory effect on ERα is not resolved. We have recently reported that ERβ, a second type of ER, is involved in the Δ 9 -THC abrogation of E2/ERα-mediated transcriptional activity. Here we discuss the possible mechanism(s) of the Δ 9 -THC-mediated disruption of E2/ERα signaling by presenting our recent findings as well.

Bisphenol AF as an Inducer of Estrogen Receptor β (ERβ): Evidence for Anti-estrogenic Effects at Higher Concentrations in Human Breast Cancer Cells

“…17,23) We previously reported that Δ 9 -THC had the potential to abrogate E2/ERα signaling in MCF-7 cells by up-regulating ERβ, which resulted in the inhibition of cell proliferation, and also that Δ 9 -THC required the co-existence of ERα/ERβ to evoke its anti-proliferative effects. 17,29) Furthermore, Gustafsson and his colleagues showed that ERβ suppressed E2/ERα-mediated uterine progression in immature mice. 30) Although we observed the anti-estrogenic nature of BPAF in breast cancer cell lines (in vitro), BPAF may induce unwanted events via the perturbation of estrogen signaling after its accumulation in certain normal tissues.…”

HU-210, a synthetic analog of ∆⁹-THC, is not a modifier of estrogen signaling in MCF-7 human breast cancer cells

“…As we reported previously, the inhibitory efficacy of HU-210 on cell viability was more potent than that of ∆ 9 -THC (i.e., IC 50 = 34.5 μM) (Takeda et al, 2013). In this study, ∆ 9 -THC was utilized as a positive control in order to analyze the anti-estrogenic potential of HU-210 for E2/ ERα signaling (Takeda et al, 2013;Takeda, 2014). Based on their IC 50 values, we subsequently investigated the effects of the two cannabinoids on E2-driven ERα activation.…”

“…Martín-Calderón et al (1998) reported that HU-210 induced a set of endocrine alterations, such as plasma hormones including growth, luteinizing, and follicle-stimulating hormones, at doses 50 -200-fold lower than those required for ∆ 9 -THC in adult female rats. These effects of cannabinoids appear to be triggered by their activation of CB receptors; however, since the ∆ 9 -THC-mediated upregulation of ERβ was not negated by specific antagonists for CB1 and CB2 (Takeda, 2014), possible requirement(s) for the up-regulation of ERβ may not involve CB receptors. As clearly shown in Fig.…”

“…Thus, the expression levels of ERβ are one of the key determinants for cellular responses mediated by E2/ERα. Some (environmental) chemicals, such as ∆ 9 -tetrahydrocannabinol (∆ 9 -THC), exert endocrine-disrupting effects, such as anti-estrogenic actions, in animals and humans (in vivo) as well as in in vitro cell systems without directly interacting with ERα (Ruh et al, 1997;Cheng et al, 2012;Takeda et al, 2013;Takeda, 2014). Therefore, modulators that affect the expression of ERβ may be endocrine disrupters.…”

“…Among the biological activities of ∆ 9 -THC, its accepted endocrine-disrupting effects, such as "anti-estrogenic activity", have been the main topic of research for a long period of time (Nir et al, 1973;Smith and Asch, 1984;Brown and Dabs, 2002;Morgan et al, 2012). We previously reported that the anti-estrogenic activities of ∆ 9 -THC may be mediated through the up-regulation of ERβ by the cannabinoid itself (Takeda et al, 2013;Takeda, 2014). However, we are currently unable to conclude whether the function of ∆ 9 -THC also applies to other cannabinoids.…”