Intestinal trefoil factor confers colonic epithelial resistance to apoptosis.
Intestinal trefoil factor (ITF) is an essential regulator of colonic epithelial restitution, the rapid migration of colonocytes over mucosal wounds. High levels of ITF are frequently present in colorectal cancers and derived cell lines. Mucosal restitution requires the detachment of epithelium from substrate, which would be expected to induce apoptosis. However, mice deficient in ITF showed an increase in colonocyte apoptosis unaccompanied by changes in expression of receptor-related (TNFR/Fas) or stress-related (Bcl-family) cell death regulators. An ITF-expressing colonic (HT-ITF1) cell line was resistant to apoptosis induced by serum starvation and ceramide. Exogenous ITF also protected another human colonic carcinoma-derived cell line (HCT116) and a nontransformed rat intestinal epithelial cell line (IEC-6) from apoptosis. This effect was abrogated by wortmannin and tyrphostin A25, indicating the potential involvement of phosphatidylinositol 3-kinase and epidermal growth factor (EGF) receptor activation. Expression of phosphorylated Akt, which lies downstream of phosphatidylinositol 3-kinase activation, was elevated in this HT-29-ITF line. p53-dependent cell death in the AGS human gastric cancer cell line after etoposide was similarly inhibited by transient expression of ITF but not a C-terminal truncation mutant of ITF, and it required functional phosphatidylinositol 3-kinase and EGF receptor. These findings support a central role for ITF in the maintenance of intestinal mucosal continuity, and conversely demonstrate the potential for ITF expression to confer resistance of colorectal tumors to therapy.
Taupin
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DR
Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, 55 Fruit Street, GRJ-719, Boston, MA 02114-2696, USA. d.taupin@pmci.unimelb.edu.au
Kinoshita
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K
Podolsky
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D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D003106:Colon / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D003110:Colonic Neoplasms / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D004789:Enzyme Activation / Q000187:drug effects; D066246:ErbB Receptors / Q000502:physiology; D015870:Gene Expression; D019254:Genes, bcl-2 / Q000235:genetics; D006133:Growth Substances / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009077:Mucins; D009124:Muscle Proteins; D009479:Neuropeptides; D010455:Peptides / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt; D012313:RNA / Q000235:genetics / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000502:physiology; D000071164:Trefoil Factor-2; D000071165:Trefoil Factor-3; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
D064413:3-Phosphoinositide-Dependent Protein Kinases; D066246:ErbB Receptors; D006133:Growth Substances; D009077:Mucins; D009124:Muscle Proteins; D009479:Neuropeptides; D010455:Peptides; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012313:RNA; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; D000071164:Trefoil Factor-2; D000071165:Trefoil Factor-3; D016159:Tumor Suppressor Protein p53; C099037:TFF3 protein, rat; C494918:AKT1 protein, human