mTOR as a positive regulator of tumor cell responses to hypoxia.
Rapamycin is a clinically approved immunosuppressive agent that has recently shown promising antitumor activities in human patients. In contrast to many conventional chemotherapeutic agents, rapamycin displays a remarkably high level of selectivity for certain types of tumors. The pharmacological activities of rapamycin are attributable to the functional inhibition of a single target protein, termed the mammalian target of rapamycin (mTOR). Because mTOR is widely expressed in both normal and transformed cells, variations in mTOR expression levels are likely not a primary determinant of tumor sensitivity to rapamycin. However, recent studies highlighted an intriguing link between cancer cell sensitivity to rapamycin and deregulated signaling through the phosphoinositide (PI) 3-kinase pathway. These findings have prompted a search for cancer-related responses that are jointly regulated by the PI 3-kinase signaling cascade and mTOR. The oxygen-regulated transcription factor, hypoxia-induced factor (HIF)-1, has emerged as a candidate target for both of these two highly interactive signaling proteins. Here we review evidence that mTOR functions as a positive regulator of HIF-1-dependent responses to hypoxic stress in human cancer cells.
Abraham
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Program in Signal Transduction Research, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. abraham@burnham.org
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D015687:Cell Hypoxia / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009369:Neoplasms / Q000201:enzymology* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D011494:Protein Kinases / Q000378:metabolism / Q000502:physiology*; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000502:physiology; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D014157:Transcription Factors; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus