The role of the Akt/mTOR pathway in tobacco carcinogen-induced lung tumorigenesis.
Lung cancer is the leading cause of cancer-related death in the United States, and 85 to 90% of lung cancer cases are associated with tobacco use. Tobacco components promote lung tumorigenesis through genotoxic effects, as well as through biochemical modulation of signaling pathways such as the Akt/mammalian target of rapamycin (mTOR) pathway that regulates cell proliferation and survival. This review will describe cell surface receptors and other upstream components required for tobacco carcinogen-induced activation of Akt and mTOR. Preclinical studies show that inhibitors of the Akt/mTOR pathway inhibit tumor formation in mouse models of carcinogen-induced lung tumorigenesis. Some of these inhibitors will be highlighted, and their clinical potential for the treatment and prevention of lung cancer will be discussed.
Memmott
Regan M
RM
Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20889, USA.
Dennis
Phillip A
PA
D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D006801:Humans; D007211:Indoles / Q000627:therapeutic use; D007294:Inositol / Q000627:therapeutic use; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012402:Rotenone / Q000031:analogs & derivatives / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000627:therapeutic use; D012907:Smoking; D058570:TOR Serine-Threonine Kinases
D002273:Carcinogens; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; D012402:Rotenone; D007294:Inositol; C016517:indole-3-carbinol; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C107676:deguelin; D020123:Sirolimus