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Cited by 400Cell death mechanisms and regulationCancer, Hypoxia, and MetabolismCancer-related Molecular Pathways

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

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Erler, Janine T., Cawthorne, Christopher J., Williams, Kaye J., Koritzinsky, Marianne, Wouters, Bradley G., Wilson, Clare, Miller, Crispin, Demonacos, Costas +2 more·2004·Molecular and Cellular Biology
DOI 10.1128/mcb.24.7.2875-2889.2004PMC PMC371100
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Abstract

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.

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  • HIF1/2 inhibitors might be effective in combination with conventional chemotherapy.

    “Taken together, these data on the role of HIFs in therapeutic resistance suggest that HIF1/2 inhibitors might be effective in combination with conventional chemotherapy (Unruh et al., 2003;Erler et al., 2004;Brown et al., 2006;Nardinocchi et al., 2009;Roberts et al., 2009;He et al., 2012;Zhao et al., 2014).”

    From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Erler et al., 2004

    The Results report that hypoxia reduced drug responsiveness and that restoring Bid increased sensitivity to etoposide. The Discussion (page unavailable) says HIF-1-dependent Bid down-regulation provides a rationale for targeting HIF-1. The paper does not address HIF-2 inhibitors or explicitly propose combining HIF inhibitors with conventional chemotherapy. (LLM, conf=0.86)

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Cited by

Sorted by citations

Authors
Erler, J. T., Cawthorne, C. J., Williams, K. J., Koritzinsky, M., Wouters, B. G., Wilson, C., Miller, C., Demonacos, C., Stratford, I. J., & Dive, C.
Affiliations
  • University of Manchester (GB)
  • Maastricht University (NL)
  • Grow Research Institute, University of Maastricht, Maastricht, The Netherlands
  • Cancer Research UK Manchester Institute (GB)
Corresponding author
Dive, Caroline
ORCID
Venue
Molecular and Cellular Biology
Publisher
Informa UK Limited
Published
2004-04-01
Volume
24
Issue
7
Pages
2875-2889
ISSN
  • 0270-7306 (ISSN-L)
  • 1098-5549
DOI
10.1128/mcb.24.7.2875-2889.2004
PMC
PMC371100
OpenAlex
W2022501326
Cited by
400
References
1
Citations by year
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FWCI
8.31
Type
journal article
Language
en
Open access
Licence
journals.asm.org/non-commercial-tdm-license (tdm)
Locations
  • Molecular and Cellular Biology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Cancer Research UK
  • Research Councils UK
  • Biotechnology and Biological Sciences Research Council
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Keywords
tumor hypoxia, Bid, Bax, Bad, Bcl-2 family proteins, apoptosis, HIF-1, HIF-1α, hypoxia response element, drug resistance, chemoresistance, radiotherapy resistance, colon cancer, translation efficiency, etoposide sensitivity, topoisomerase II inhibitors
MeSH terms
Animals, Hypoxia, Carrier Proteins, DNA-Binding Proteins, Etoposide, Female, Humans, Mice, Nude, Neoplasms, Nuclear Proteins, Promoter Regions, Genetic, Protein Binding, Proto-Oncogene Proteins, Transcription Factors, Transplantation, Heterologous, Down-Regulation, Apoptosis, Drug Resistance, Neoplasm, Proto-Oncogene Proteins c-bcl-2, Nucleic Acid Synthesis Inhibitors, Cell Line, Tumor, BH3 Interacting Domain Death Agonist Protein, bcl-2-Associated X Protein, Mice, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit

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