Tobacco carcinogen-induced cellular transformation increases activation of the phosphatidylinositol 3'-kinase/Akt pathway in vitro and in vivo.
The role of the phosphatidylinositol 3'-kinase (PI3K)/Akt pathway during tobacco carcinogen-induced transformation is unknown. To address this question, we evaluated this pathway in isogenic immortalized or tumorigenic human bronchial epithelial cells in vitro, as well as in progressive murine lung lesions induced by a tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Compared with immortalized cells, tumorigenic cells had greater activation of the PI3K/Akt pathway, enhanced survival, and increased apoptosis in response to inhibition of the pathway. In vivo, increased activation of Akt and mammalian target of rapamycin was observed with increased phenotypic progression. Collectively, these results support the hypothesis that maintenance of Akt activity is necessary for survival of preneoplastic as well as transformed lung epithelial cells and suggest that inhibition of the PI3K/Akt pathway might be a useful approach to arrest lung tumorigenesis.
West
Kip A
KA
Cancer Therapeutics Branch, Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA.
Linnoila
Ilona R
IR
Belinsky
Steven A
SA
Harris
Curtis C
CC
Dennis
Phillip A
PA
D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D002460:Cell Line; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D004789:Enzyme Activation; D006801:Humans; D008168:Lung; D008175:Lung Neoplasms / Q000201:enzymology / Q000473:pathology; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011230:Precancerous Conditions / Q000201:enzymology / Q000473:pathology; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D020545:Respiratory Mucosa; D014026:Nicotiana / Q000009:adverse effects*
D002273:Carcinogens; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; C494918:AKT1 protein, human