Hypoxia-mediated down-regulation of Bid and Bax in tumors occurs via hypoxia-inducible factor 1-dependent and -independent mechanisms and contributes to drug resistance.
Authors
Erler, Janine TCawthorne, Christopher
Williams, Kaye J
Koritzinsky, Marianne
Wouters, Bradley G
Wilson, Claire L
Miller, Crispin J
Demonacos, Costas
Stratford, Ian J
Dive, Caroline
Affiliation
Cellular and Molecular Pharmacology Group, Bioinformatics Group, Paterson Institute for Cancer Research, Manchester M20 4BX, United Kingdom.Issue Date
2004-04
Metadata
Show full item recordAbstract
Solid tumors with disorganized, insufficient blood supply contain hypoxic cells that are resistant to radiotherapy and chemotherapy. Drug resistance, an obstacle to curative treatment of solid tumors, can occur via suppression of apoptosis, a process controlled by pro- and antiapoptotic members of the Bcl-2 protein family. Oxygen deprivation of human colon cancer cells in vitro provoked decreased mRNA and protein levels of proapoptotic Bid and Bad. Hypoxia-inducible factor 1 (HIF-1) was dispensable for the down-regulation of Bad but required for that of Bid, consistent with the binding of HIF-1alpha to a hypoxia-responsive element (positions -8484 to -8475) in the bid promoter. Oxygen deprivation resulted in proteosome-independent decreased expression of Bax in vitro, consistent with a reduction in global translation efficiency. The physiological relevance of Bid and Bax down-regulation was confirmed in tumors in vivo. Oxygen deprivation resulted in decreased drug-induced apoptosis and clonogenic resistance to agents with different mechanisms of action. The contribution of Bid and/or Bax down-regulation to drug responsiveness was demonstrated by the relative resistance of normoxic cells that had no or reduced expression of Bid and/or Bax and by the finding that forced expression of Bid in hypoxic cells resulted in increased sensitivity to the topoisomerase II inhibitor etoposide.Citation
Hypoxia-mediated down-regulation of Bid and Bax in tumors occurs via hypoxia-inducible factor 1-dependent and -independent mechanisms and contributes to drug resistance. 2004, 24 (7):2875-89 Mol. Cell. Biol.Journal
Molecular and Cellular BiologyPubMed ID
15024076Type
ArticleLanguage
enISSN
0270-7306Collections
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