Modulation of Delta9-tetrahydrocannabinol-induced MCF-7 breast cancer cell growth by cyclooxygenase and aromatase.Toxicology. 2009 May 02; 259(1-2):25-32.T
Delta(9)-Tetrahydrocannabinol (Delta(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. Delta(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 17beta-estradiol (E(2)), the interaction of Delta(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 Delta(9)-THC-mediated MCF-7 cell proliferation. It was shown that Delta(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 Delta(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 Delta(9)-THC-mediated MCF-7 cell proliferation. On the other hand, Delta(9)-THC-induced MCF-7 cell growth was elevated by two kinds of aromatase inhibitors. Taken together with the evidence that Delta(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 Delta(9)-THC are mediated by the product(s) of COX-2 except for PGE(2), (2) the action of Delta(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 Delta(9)-THC.