Submitted on December 22, 2006
Accepted on July 13, 2007
PGE2 inhibits apoptosis in human adenocarcinoma Caco-2 cell line through RAS-PI3-kinase association and cAMP dependent Kinase A activation
Vincenza Leone1, Antonella di Palma1, Paolo Ricchi2, Fabio Acquaviva1, Maria Giannouli1, Anna Maria Di Prisco1, Francesca Iuliano1, and Angela M. Acquaviva1*
1 Dipartimento di Biologia e Patologia Cellulare e Molecolare, Universita "Federico II", Naples, Italy
2 Dipartimento di Biologia e Patologia Cellulare e Molecolare, Universita "Federico II", Naples, Italy; Centro di Microcitemia "A.Mastrobuoni", Azienda Cardarelli, Italy
* To whom correspondence should be addressed. E-mail: angacqua{at}unina.it.
Prostaglandin E2 plays a critical role in colorectal carcinogenesis. We have previously shown that COX-2 expression and PGE2 synthesis are mediated by IGF-II/IGF-I receptor signalling in Caco-2 cell line and that the pathway of PI3-K/AKT protects the cell from apoptosis. In the present study, we demonstrate that PGE2 has the ability to increase RAS and PI3-K association and decrease the level of apoptosis in the same experimental system. The effect of PGE2 on PI3-K/RAS association is dependent on the activation of EP4 receptor, the increase of cAMP levels and the activation of kinase A. In fact, treatment of cells with the pKA inhibitor H89 decreases the association of RAS and PI3-K, and RAS-associated PI3-K activity. pKA inhibitor H89 is able to decrease threonine phosphorylation of AKT and to increase serine phosphorylation of AKT by p38 Map kinase and counteracts the cytoprotective effect induced by PGE2. In addition, PGE2 are able to activate p38 Map Kinase and the inhibition of p38 Map kinase with SB203580 specif inhibitor or with dominant negative MKK6K is able to revert the apoptotic effect of H89 and serine phosphorylation of AKT. The effect of PGE2 on Caco-2 cell survival through pKA activation is mediated and regulated by the balance of threonine/serine phosphorylation of AKT by p38 kinase and PI3-K. In conclusion, our data elucidate a novel mechanism for regulation of colon cancer cell survival and provide evidences for new combinatory treatments of colon cancer.
