Cannabinoid receptor agonist-induced apoptosis of human prostate cancer cells LNCaP proceeds through sustained activation of ERK1/2 leading to G1 cell cycle arrest.

摘要: We have recently shown that the expression levels of both cannabinoid receptors CB(1) and CB(2) are higher in human prostate cancer cells than normal epithelial cells, treatment LNCaP with WIN-55,212-2 (a mixed CB(1)/CB(2) agonist) resulted inhibition cell growth induction apoptosis (Sarfaraz, S., Afaq, F., Adhami, V. M., Mukhtar, H. (2005) Cancer Res. 65, 1635-1641). This study was conducted to understand mechanistic basis these effects. Treatment (1-10 microm; 24 h) in: (i) an arrest G(0)/G(1) phase cycle; (ii) p53 p27/KIP1; (iii) down-regulation cyclins D1, D2, E; decrease cdk-2, -4, -6; (iv) protein pRb; (v) E2F (1-4); (vi) DP1 DP2. Similar effects were also observed when androgen-independent PC3 treated (5-30 microm). further sustained up-regulation ERK1/2 PI3k/Akt pathways WIN-55,212-2-treated cells. Inhibition abrogated WIN-55,212-2-indued death suggesting activation leads cycle dysregulation subsequently leading apoptosis. Further, a dose-dependent increase Bax/Bcl-2 ratio such way favors The proceeded through caspases 3, 6, 7, 9 cleavage poly (ADP-ribose) polymerases. Based on data we suggest receptor agonists should be considered as novel agents for management cancer.