Inhibition of apoptosis in normal and transformed intestinal epithelial cells by cAMP through induction of inhibitor of apoptosis protein (IAP)-2.
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)E2 receptors is a contributing factor. The major PGE2 receptors on epithelial cells, EP2 and 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 PGE2 addition, suggesting that COX-2-promoted antiapoptosis is mediated by release of PGE2 and 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.
Nishihara
Hiroshi
H
Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093, USA.
Kizaka-Kondoh
Shinae
S
Insel
Paul A
PA
Eckmann
Lars
L
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology*; D001483:Base Sequence; D053148:Caspase 3; D061945:Caspase Inhibitors; D002460:Cell Line; D002461:Cell Line, Transformed; D000242:Cyclic AMP / Q000819:agonists* / Q000378:metabolism; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000378:metabolism / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology / Q000187:drug effects; D007527:Isoenzymes / Q000378:metabolism; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D014764:Viral Proteins / Q000096:biosynthesis* / Q000235:genetics
D061945:Caspase Inhibitors; D051034:Inhibitor of Apoptosis Proteins; D007527:Isoenzymes; D008565:Membrane Proteins; D012333:RNA, Messenger; D014764:Viral Proteins; C086430:inhibitor of apoptosis, Nucleopolyhedrovirus; D000242:Cyclic AMP; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D015232:Dinoprostone