NAD+-linked 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is responsible for the catabolism of prostaglandins in a variety of cell types such as inflammation an dtumorigenesis. In this study we showed that forced overexpression of 15-PGDH in human cholangiocarcinoma cells (CCLP1) suppressed tumor cell growth, invasion and clonogenic formation capacity. In contrast, 15-PGDH knockdown in CCLP1 cells enhanced tumor cell growth, invasion and clonogenic formation. Flow cytometry analysis revealed that 15-PGDH overexpression induced cell cycle arrest at G1/S checkpoint. When implanted into SCID mice, 15-PGDH overexpressed CCLP1 cells formed smaller xenograft tumors, whereas 15-PGDH-depleted cells formed larger xenograft tumors when compared with each of the corresponding controls (p<0.01). In addition, intratumoral injection of an adenoviral vector expressing 15-PGDH (pAd-15-PGDH) significantly inhibited the growth of cholangiocarcinoima in SCID mice. Western blot analysis showed that 15-PGDH induced the expression of TAp63, a key tumor suppressive gene. Furthermore, 15-PGDH induced the phosphorylation of Smad2/3 and enhanced the interaction between p53 and pSmad2/3 in CCLP1 cells; the pSmad2/3 and p53 binding complex appeared to play a key role for the induction of TAp63 expression. Taken together, our data suggest that 15-PGDH inhibits cholangiocarcinoma growth and this effect is at least in part through pSmad2/3 and p53-mediated induction of TAp63.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1179. doi:1538-7445.AM2012-1179