Modulation of Δ 9-tetrahydrocannabinol-induced MCF-7 breast cancer cell growth by cyclooxygenase and aromatase

Abstract

Δ 9-Tetrahydrocannabinol (Δ 9-THC), a major constituent of marijuana, has been shown to stimulate the growth of MCF-7 breast cancer cells through cannabinoid receptor-independent signaling [Takeda, S., Yamaori, S., Motoya, E., Matsunaga, T., Kimura, T., Yamamoto, I., Watanabe, K., 2008. Δ 9-Tetrahydrocannabinol enhances MCF-7 cell proliferation via cannabinoid receptor-independent signaling. Toxicology 245, 141–146]. Although the growth of MCF-7 cells is known to be stimulated by 17β-estradiol (E 2), the interaction of Δ 9-THC and E 2 in MCF-7 cell growth is not fully clarified so far. In the present study, by using E 2-sensitive MCF-7 cells that have expressed cyclooxygenase-2 (COX-2) and cytochrome P450 19 (aromatase), we studied whether or not COX-2 and aromatase are involved in Δ 9-THC-mediated MCF-7 cell proliferation. It was shown that Δ 9-THC-induced MCF-7 cell growth was inhibited by COX-2 inhibitors and was stimulated by arachidonic acid (a COX substrate). However, the growth of MCF-7 cells induced by Δ 9-THC was not stimulated by PGE 2, and the expression of aromatase was not affected by COX-2 inhibitors, arachidonic acid, and PGE 2, suggesting that there is a disconnection between COX-2 (PGE 2) and aromatase in Δ 9-THC-mediated MCF-7 cell proliferation. On the other hand, Δ 9-THC-induced MCF-7 cell growth was elevated by two kinds of aromatase inhibitors. Taken together with the evidence that Δ 9-THC-induced MCF-7 cell proliferation was interfered with testosterone (an aromatase substrate) and exogenously provided E 2, it is suggested that (1) the growth stimulatory effects of Δ 9-THC are mediated by the product(s) of COX-2 except for PGE 2, (2) the action of Δ 9-THC is modulated by E 2, and (3) COX-2 and aromatase are individually engaged in the proliferation of MCF-7 cells induced by Δ 9-THC.