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

Janine Terra Erler; Christopher J Cawthorne; Kaye J Williams; Marianne Koritzinsky; Bradley G Wouters; Clare Wilson; Crispin Miller; Costas Demonacos; Ian J Stratford; Caroline Dive

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

Janine Terra Erler, Christopher J Cawthorne, Kaye J Williams, Marianne Koritzinsky, Bradley G Wouters, Clare Wilson, Crispin Miller, Costas Demonacos, Ian J Stratford, Caroline Dive

294 Citations (Scopus)

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.

Original language	English
Journal	Molecular and Cellular Biology
Volume	24
Issue number	7
Pages (from-to)	2875-89
Number of pages	15
ISSN	0270-7306
Publication status	Published - Apr 2004
Externally published	Yes

Keywords

Animals
Anoxia
Apoptosis
BH3 Interacting Domain Death Agonist Protein
Carrier Proteins
Cell Line, Tumor
DNA-Binding Proteins
Down-Regulation
Drug Resistance, Neoplasm
Etoposide
Female
Humans
Hypoxia-Inducible Factor 1
Hypoxia-Inducible Factor 1, alpha Subunit
Mice
Mice, Nude
Neoplasms
Nuclear Proteins
Nucleic Acid Synthesis Inhibitors
Promoter Regions, Genetic
Protein Binding
Proto-Oncogene Proteins
Proto-Oncogene Proteins c-bcl-2
Transcription Factors
Transplantation, Heterologous
bcl-2-Associated X Protein

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Cite this

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. (2004). 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. Molecular and Cellular Biology, 24(7), 2875-89.

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. / Erler, Janine Terra; Cawthorne, Christopher J; Williams, Kaye J et al.

In: Molecular and Cellular Biology, Vol. 24, No. 7, 04.2004, p. 2875-89.

Research output: Contribution to journal › Journal article › Research › peer-review

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title = "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",

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.",

keywords = "Animals, Anoxia, Apoptosis, BH3 Interacting Domain Death Agonist Protein, Carrier Proteins, Cell Line, Tumor, DNA-Binding Proteins, Down-Regulation, Drug Resistance, Neoplasm, Etoposide, Female, Humans, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit, Mice, Mice, Nude, Neoplasms, Nuclear Proteins, Nucleic Acid Synthesis Inhibitors, Promoter Regions, Genetic, Protein Binding, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-bcl-2, Transcription Factors, Transplantation, Heterologous, bcl-2-Associated X Protein",

author = "Erler, {Janine Terra} and Cawthorne, {Christopher J} and Williams, {Kaye J} and Marianne Koritzinsky and Wouters, {Bradley G} and Clare Wilson and Crispin Miller and Costas Demonacos and Stratford, {Ian J} and Caroline Dive",

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language = "English",

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journal = "Molecular and Cellular Biology",

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T1 - 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

AU - Erler, Janine Terra

AU - Cawthorne, Christopher J

AU - Williams, Kaye J

AU - Koritzinsky, Marianne

AU - Wouters, Bradley G

AU - Wilson, Clare

AU - Miller, Crispin

AU - Demonacos, Costas

AU - Stratford, Ian J

AU - Dive, Caroline

PY - 2004/4

Y1 - 2004/4

N2 - 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.

AB - 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.

KW - Animals

KW - Anoxia

KW - Apoptosis

KW - BH3 Interacting Domain Death Agonist Protein

KW - Carrier Proteins

KW - Cell Line, Tumor

KW - DNA-Binding Proteins

KW - Down-Regulation

KW - Drug Resistance, Neoplasm

KW - Etoposide

KW - Female

KW - Humans

KW - Hypoxia-Inducible Factor 1

KW - Hypoxia-Inducible Factor 1, alpha Subunit

KW - Mice

KW - Mice, Nude

KW - Neoplasms

KW - Nuclear Proteins

KW - Nucleic Acid Synthesis Inhibitors

KW - Promoter Regions, Genetic

KW - Protein Binding

KW - Proto-Oncogene Proteins

KW - Proto-Oncogene Proteins c-bcl-2

KW - Transcription Factors

KW - Transplantation, Heterologous

KW - bcl-2-Associated X Protein

M3 - Journal article

C2 - 15024076

SN - 0270-7306

VL - 24

SP - 2875

EP - 2889

JO - Molecular and Cellular Biology

JF - Molecular and Cellular Biology

IS - 7

ER -

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

Abstract

Keywords

UN SDGs

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