Insulin-like growth factor-I has a biphasic effect on colon carcinoma cells through transient inactivation of forkhead1, initially mitogenic, then mediating growth arrest and differentiation.
IGF-I stimulates intestinal cell differentiation after initiating a short proliferative burst, similar to its effect on muscle cell differentiation. Levels of IGF-I attainable in serum (10-20 ng/ml) induced transient growth stimulation of colon carcinoma cells, then growth arrest. When IGF-I functioned as a mitogen, it blocked differentiation. Intestinal cell differentiation occurred once cells had undergone the IGF-I-initiated growth arrest and IGF-I and butyrate acted synergistically to induce maturation markers. IGF-I induces NIH-3T3 cell proliferation and survival by activating the kinase akt, which in turn inhibits various apoptotic mediators and the forkhead family of transcription factors, which mediate expression of p27(kip1). Promoter reporter assays demonstrated that forkhead1 mediates transcription of p27(kip1) in colon carcinoma cells. The mitogenic effects of IGF-I on 4 colon carcinoma cell lines were transient because the inactivating phosphorylation of forkhead1 by akt was short-lived. This allowed transcriptional upregulation of the cdk inhibitor p27(kip1), with a resulting growth arrest. In contrast, in NIH-3T3 cells treated in parallel with identical IGF-I levels, forkhead phosphorylation levels were sustained; thus, no increase in p27(kip1) levels was seen and cells continued to proliferate. Intestinal epithelial cells in vivo undergo a limited number of divisions, then growth arrest and completion of their maturation. IGFs found in intestinal tissue may control the timing of this process. In addition, colon cancers may have developed strategies to overcome IGF-I-mediated growth arrest. Earlier (Kansra et al., Int J Cancer 2000;87:373-8), we found that levels of IGFBP-3 were elevated at least 2-fold in 70% of resected colon cancers compared with adjacent normal tissue. In the current study, growth inhibition by IGF-I and IGF-II was blocked by concurrent addition of IGFBP-3, implying that colon cancers with elevated IGFBP-3 levels would be selected for in vivo because they could bind and inactivate high serum IGF-I levels and continue to proliferate.
Ewton
Daina Z
DZ
Pathology Department, Upstate Medical University, State University of New York, Syracuse, NY 13210, USA.
Kansra
Sanjay
S
Lim
Seunghwan
S
Friedman
Eileen
E
D000818:Animals; D015152:Blotting, Northern; D002087:Butyrates / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051858:Forkhead Transcription Factors; D006801:Humans; D007124:Immunoenzyme Techniques; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000494:pharmacology*; D051379:Mice; D008934:Mitogens / Q000494:pharmacology; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D051025:bcl-Associated Death Protein
C494819:BAD protein, human; C494820:Bad protein, mouse; D002087:Butyrates; D002352:Carrier Proteins; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D051858:Forkhead Transcription Factors; D008934:Mitogens; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D051025:bcl-Associated Death Protein; D050760:Cyclin-Dependent Kinase Inhibitor p27; D007334:Insulin-Like Growth Factor I; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt