Induction of the antitumorigenic NSAID‐activated gene (NAG‐1) in synthetic hexahydrocannabinol‐induced apoptosis of human colorectal cancer cells

Abstract

Non‐steroidal anti‐inflammatory drug (NSAID)‐activated gene (NAG‐1) is a transforming growth factor (TGF)‐β superfamily member that has pro‐apoptotic and anti‐tumorigenic activities. Cannabinoids have recently been extensively studied for their anti‐tumoral activity, and NAG‐1 has been shown to be up‐regulated by delta 9‐tetrahydrocannabinol. The present study investigated whether a synthetic hexahydrocannabinol, Yong‐8, influences NAG‐1 expression and apoptosis in human colorectal cancer cells, HCT‐116 (wild‐type p53) and HT‐29 (p53 mutant). Yong‐8 induced NAG‐1 protein and mRNA expressions in both cell lines. Concomitantly, Yong‐8 induced apoptosis of both HT‐29 and HCT‐116 in a concentration‐dependent manner. Interestingly, Yong‐8 increased p53 protein expression in both cell lines irrespective of their p53 status. Moreover, inhibition of p53 using antisense oligonucleotide caused a significant decrease in NAG‐1 protein expression and apoptosis in both cell lines under the same conditions. The present study demonstrates for the first time that Yong‐8, a synthetic hexahydrocannabinol, induces apoptosis in colon cancer cells. Taken together, our results suggest that hexahydrocannabinol induces colon cancer apoptosis via up‐regulation of NAG‐1 expression which is regulated by p53.