Insulin-like growth factor 1 receptor enhances invasion and induces resistance to apoptosis of colon cancer cells through the Akt/Bcl-x(L) pathway.
Colon cancer overexpresses insulin-like growth factor 1 (IGF1) and insulin-like growth factor 1 receptor (IGF1-R), as compared with normal or adenomatous mucosa, and it has been postulated that colorectal cancer cells depend on the IGF1/IGF1-R pathway for their growth and progression. In this study, using the human colon cancer cell line HCT116, we find that established HCT116/IGF1-R transfectants exhibit a more aggressive transformed phenotype than the parental cell line, as demonstrated by their higher proliferation rate in response to IGF1, higher degree of anchorage-independent growth, resistance to serum deprivation-induced apoptosis, and higher migratory capability in a monolayer "wounding assay." When injected into nude mice, HCT116/IGF1-R transfectants were highly invasive and produced distant metastases, whereas the parental cell did not. Moreover, the overexpression of IGF1-R in these cells was associated with IGF1-R-induced activation of Akt and up-regulation of the antiapoptotic protein Bcl-x(L). We also show that Akt pathway mediates IGF1-R-induced Bcl-x(L) expression at transcriptional level. Our data demonstrate, for the first time, that IGF1-R/Akt/Bcl-x(L) pathway may contribute to a more aggressive malignant phenotype, in a subset of colorectal cancers.
Sekharam
Madhavi
M
Department of Interdisciplinary Oncology, Moffitt Cancer Center and Research Institute, University of South Florida College of Medicine, 12902 Magnolia Drive, Tampa, FL 33612, USA.
Zhao
Haiyan
H
Sun
Mei
M
Fang
Quan
Q
Zhang
Qingbo
Q
Yuan
Zengqiang
Z
Dan
Han C
HC
Boulware
David
D
Cheng
Jin Q
JQ
Coppola
Domenico
D
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002455:Cell Division / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D014183:Transplantation, Heterologous; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D017526:Receptor, IGF Type 1; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt