Cannabinoid Receptors: A Novel Target for Treating Prostate Cancer.

摘要

Recently we have shown that expression levels of both cannabinoid receptors CB and CB12 are higher in human prostate cancer cells than in normal prostate epithelial cells and treatment of LNCaP cells with WIN-55,212-2 (a mixed CB1/CB2 agonist) resulted in inhibition of cell growth and induction of apoptosis. Based on these data we suggested that WlN-55,212-2 or other non- habit forming cannabinoid receptor agonists could be developed as novel therapeutic agents for the treatment of prostate cancer (Sarfaraz et al., 2005). To understand the mechanistic basis of these effects here we show that WIN-55,212-2 (1-10 muM) treatment of LNCaP cells resulted in (i) upregulation p27 /KIP1, (ii) down-regulation of cyclin E, D1 and D2 (iii) decrease in the protein expression of cyclin-dependent kinase 2,4, and 6, (iv) downregulation of pRb, (v) decrease in E2F (1-4) family of transcriptional factors and their heterodimeric partners DP-1 and DP-2, (vi) upregulation of Bax with concomitant downregulation of Bcl-2 favoring shift in Bax/Bcl-2 ratio more towards apoptosis (vii) induction of apoptosis inducing factor (viii) down regulation of caspases 3, 6, 7 and 9 and (ix) cleavage of poly (ADP-ribose) polymerase (PARP). Taken together our data shows the involvement of two distinct pathways through which WIN-55,212-2 induces apoptosis. In the first pathway G1 arrest and cell cycle dysregulation leads to the induction of apoptosis and in the second pathway apoptosis is mediated via activation of caspases. These data could lead to the development of novel mechanism based approaches for the treatment of prostate cancer.