Inhibition of Apoptosis in Normal and Transformed Intestinal Epithelial Cells by cAMP through Induction of Inhibitor of Apoptosis Protein (IAP)-2

• Published in: Proceedings of the National Academy of Sciences - PNAS 2003-07, Vol.100 (15), p.8921-8926
• Main Authors: Nishihara, Hiroshi, Kizaka-Kondoh, Shinae, Insel, Paul A., Eckmann, Lars
• Format: Article
• Language: English
• Subjects: Adenoma; Agonists; Animals; Antibodies; Apoptosis; Apoptosis - drug effects; Apoptosis - physiology; Base Sequence; Biological Sciences; Caspase 3; Caspase Inhibitors; Cell Line; Cell Line, Transformed; Cell lines; Cells; Colon; Colorectal cancer; Cyclic AMP - agonists; Cyclic AMP - metabolism; Cyclooxygenase 2; Dinoprostone - metabolism; Dinoprostone - pharmacology; DNA; Epithelial cells; Epithelial Cells - cytology; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Humans; Inhibitor of Apoptosis Proteins; Intestines - cytology; Intestines - drug effects; Intestines - metabolism; Isoenzymes - metabolism; Membrane Proteins; Prostaglandin-Endoperoxide Synthases - metabolism; Proteins; Rats; Reverse transcriptase polymerase chain reaction; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction; Skin; Viral Proteins - biosynthesis; Viral Proteins - genetics
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1533221100

Cyclooxygenase (COX)-2, a rate-limiting enzyme of prostaglandin (PG) production, is overexpressed in colorectal adenomas and adenocarcinomas, and its inhibition by nonsteroidal antiinflammatory drugs protects against colorectal cancer. Mechanisms of cancer promotion by COX-2 are not fully understood, but signaling through prostaglandin (PG)E2receptors is a contributing factor. The major PGE2receptors on epithelial cells, EP2and EP4, increase cAMP production, which promotes growth and inhibits apoptosis in some cell types. Here, we show that cAMP agonists, including PGE2, cholera toxin, and a membrane-permeant cAMP analog, protect normal and transformed intestinal epithelial cells from apoptosis induced by diverse stimuli. This protection is associated with cAMP-mediated, rapid induction of cellular inhibitor of apoptosis protein (c-IAP)-2 and delayed induction of LIVIN, but not of six other members of the IAP family. Concurrently and characteristic of IAP functions, the activity, but not generation, of the cleaved form of the central executioner caspase 3 is inhibited. Induction of c-IAP2 expression by cAMP agonists is accompanied by phosphorylation of cAMP response element binding protein and cAMP response element-dependent activation of transcriptional reporters. Furthermore, inhibition of COX-2 in cells overexpressing the enzyme decreases c-IAP2 expression and promotes apoptosis, both of which are reversible by PGE2addition, suggesting that COX-2-promoted antiapoptosis is mediated by release of PGE2and subsequent cAMP-dependent c-IAP2 induction. These results help to explain the cancer chemoprotective effects of nonsteroidal antiinflammatory drugs by defining a mechanism through which cAMP signaling can promote the development of colorectal and possibly other epithelial cancers by means of disruption of normal apoptotic processes.