HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 293/4/G673    most recent 00584.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Leone, V. Articles by Acquaviva, A. M. Search for Related Content PubMed PubMed Citation Articles by Leone, V. Articles by Acquaviva, A. M.

INFLAMMATION/IMMUNITY/MEDIATORS

PGE₂ inhibits apoptosis in human adenocarcinoma Caco-2 cell line through Ras-PI3K association and cAMP-dependent kinase A activation

¹Dipartimento di Biologia e Patologia Cellulare e Molecolare L. Califano, Università degli Studi di Napoli Federico II; and ²Centro di Microcitemia A. Mastrobuoni, Azienda Ospedaliera Cardarelli, Naples, Italy

Submitted 22 December 2006 ; accepted in final form 13 July 2007

PGE₂ 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 signaling in the Caco-2 cell line and that the pathway of phosphatidylinositol 3-kinase (PI3K)/Akt protects the cell from apoptosis. In the present study, we demonstrate that PGE₂ has the ability to increase Ras and PI3K association and decrease the level of apoptosis in the same experimental system. The effect of PGE₂ on PI3K/Ras association is dependent on the activation of EP4 receptor, the increase of cAMP levels, and the activation of PKA. In fact, treatment of cells with the PKA inhibitor H89 decreases the association of Ras and PI3K and Ras-associated PI3K activity. PKA inhibitor H89 is able to decrease threonine phosphorylation of Akt and to increase serine phosphorylation of Akt by p38 MAPK and counteracts the cytoprotective effect induced by PGE₂. In addition, PGE₂ is able to activate p38 MAPK and the inhibition of p38 MAPK, with SB203580 specific inhibitor or with dominant negative MKK6 kinase, 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 PI3K. 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.

colon cancer; prostaglandin E₂; Akt; protein kinase A; phosphatidylinositol 3-kinase

This article has been cited by other articles:

				A. K. Bauer and E. A. Rondini REVIEW PAPER: The Role of Inflammation in Mouse Pulmonary Neoplasia Vet. Pathol., May 1, 2009; 46(3): 369 - 390. [Abstract] [Full Text] [PDF]

				A. Greenhough, H. J.M. Smartt, A. E. Moore, H. R. Roberts, A. C. Williams, C. Paraskeva, and A. Kaidi The COX-2/PGE2 pathway: key roles in the hallmarks of cancer and adaptation to the tumour microenvironment Carcinogenesis, March 1, 2009; 30(3): 377 - 386. [Abstract] [Full Text] [PDF]

				Z. Liu, X. Wang, Y. Lu, S. Han, F. Zhang, H. Zhai, T. Lei, J. Liang, J. Wang, K. Wu, et al. Expression of 15-PGDH is downregulated by COX-2 in gastric cancer Carcinogenesis, June 1, 2008; 29(6): 1219 - 1227. [Abstract] [Full Text] [PDF]