15-PGDH inhibits hepatocellular carcinoma growth through 15-keto-PGE 2 /PPARγ-mediated activation of p21 WAF1/Cip1

Abstract

15-Hydroxyprostaglandin dehydrogenase (15-PGDH) is a key enzyme in prostaglandin (PG) metabolism. This study provides important evidence for inhibition of hepatocellular carcinoma (HCC) growth by 15-PGDH through the 15-keto-prostaglandin E 2 (15-keto-PGE 2)/peroxisome proliferator-activated receptor-γ (PPARγ)/p21 WAF1/Cip1 signaling pathway. Forced overexpression of 15-PGDH inhibited HCC cell growth in vitro, whereas knockdown of 15-PGDH enhanced tumor growth parameters. In a tumor xenograft model in severe combined immunodeficiency mice, inoculation of human HCC cells (Huh7) with overexpression of 15-PGDH led to significant inhibition of tumor growth, whereas knockdown of 15-PGDH enhanced tumor growth. In a separate tumor xenograft model in which mouse HCC cells (Hepa1-6) were inoculated into syngeneic C57BL/6 mice, intratumoral injection of adenovirus vector expressing 15-PGDH (pAd-15-PGDH) significantly inhibited xenograft tumor growth. The antitumor effect of 15-PGDH is mediated through its enzymatic product, 15-keto-PGE 2, which serves as an endogenous PPARγ ligand. Activation of PPARγ by 15-PGDH-derived 15-keto-PGE 2 enhanced the association of PPARγ with the p21 WAF1/Cip1 promoter and increased p21 expression and association with cyclin-dependent kinase 2 (CDK2), CDK4 and proliferating cell nuclear antigen. Depletion of p21 by short hairpin RNA reversed 15-PGDH-induced inhibition of HCC cell growth; overexpression of p21 prevented 15-PGDH knockdown-induced tumor cell growth. These results show a key 15-PGDH/15-keto-PGE 2 -mediated activation of PPARγ and p21 WAF1/Cip1 signaling cascade that regulates hepatocarcinogenesis and tumor progression. © 2014 Macmillan Publishers Limited.