Does endogenous fatty acid metabolism allow cancer cells to sense hypoxia and mediate hypoxic vasodilatation? Characterization of a novel molecular connection between fatty acid synthase (FAS) and hypoxia-inducible factor-1α (HIF-1α)-related expression of vascular endothelial growth factor (VEGF) in cancer cells overexpressing Her-2/neu oncogene

Javier A. Menendez, Luciano Vellon, Bharvi P. Oza, Ruth Lupu

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Her-2/neu (erbB-2) oncogene overexpression is associated with increased tumor progression and metastasis. Fatty acid synthase (FAS), the key lipogenic enzyme responsible for the endogenous synthesis of fatty acids, has been shown to be one of the genes regulated by Her-2/neu at the level of transcription, translation, and biosynthetic activity. Interestingly, we recently established that both pharmacological inhibition of FAS activity and silencing of FAS gene expression specifically suppress Her-2/neu oncoprotein expression and tyrosine-kinase activity in breast and ovarian Her-2/neu overexpressors. Unraveling the functional organization of this novel bi-directional molecular connection between Her-2/neu and FAS-dependent neoplastic lipogenesis is a major challenge that the field is only beginning to take on. Considering that Her-2/neu overexpression correlates with increased expression of the hypoxia inducible factor-1α (HIF-1α), which, in a mitogen-activated protein kinase (MAPK)-dependent manner, plays a key role in the expression of several genes including cytokines such as vascular endothelial growth factor (VEGF), we hypothesized that FAS blockade should result in a concomitant down-regulation of VEGF. Unexpectedly, the specific inhibition of the de novo fatty acid synthesis with the small-molecule inhibitor of FAS activity C75 resulted in a dramatic dose-dependent enhancement (up to 500% increase) of VEGF secretion in Her-2/neu-overexpressing SK-Br3, BT-474, and SKOV3 cancer cells. Concurrently, FAS blockade drastically activated MARK and promoted further a prominent accumulation of HIF-1α in Her-2/neu overexpressors. Moreover, U0126-induced inhibition of MAPK activity completely abolished C75-induced up-regulation of HIF-1α expression and VEGF secretion, whereas it did not modulate C75-induced down-regulation of Her-2/neu oncogene. Importantly, RNA interference (RNAi)-mediated silencing of the FAS gene recapitulated C75's effects by up-regulating VEGF secretion, MAPK activation and HIF-1α expression. Therefore, it appears that perturbation of cancer-associated endogenous fatty metabolism triggers a "hypoxia-like" (oxygen-independent) condition that actively rescues Her-2/neu-dependent MARK → HIP-1α → VEGF cascade. It is tempting to suggest that an intact FAS-catalyzed endogenous fatty acid metabolism is a necessary metabolic adaptation to support the enhanced ability of Her-2/neu-overexpressing cancer cells to survive cellular hypoxia in a HIF-α-dependent manner.

Original languageEnglish (US)
Pages (from-to)857-863
Number of pages7
JournalJournal of Cellular Biochemistry
Volume94
Issue number5
DOIs
StatePublished - Apr 1 2005
Externally publishedYes

Fingerprint

Hypoxia-Inducible Factor 1
Fatty Acid Synthases
Oncogenes
Metabolism
Vasodilation
Vascular Endothelial Growth Factor A
Fatty Acids
Cells
Neoplasms
Mitogen-Activated Protein Kinases
Genes
Down-Regulation
Gene Expression
Hypoxia
Cell Hypoxia
Lipogenesis
Hot isostatic pressing
Oncogene Proteins
Transcription
RNA Interference

Keywords

  • Angiogenesis
  • Cancer
  • erbB-2
  • Fatty acid synthase
  • Her-2/neu
  • Hypoxia
  • VEGF

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology

Cite this

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title = "Does endogenous fatty acid metabolism allow cancer cells to sense hypoxia and mediate hypoxic vasodilatation? Characterization of a novel molecular connection between fatty acid synthase (FAS) and hypoxia-inducible factor-1α (HIF-1α)-related expression of vascular endothelial growth factor (VEGF) in cancer cells overexpressing Her-2/neu oncogene",
abstract = "Her-2/neu (erbB-2) oncogene overexpression is associated with increased tumor progression and metastasis. Fatty acid synthase (FAS), the key lipogenic enzyme responsible for the endogenous synthesis of fatty acids, has been shown to be one of the genes regulated by Her-2/neu at the level of transcription, translation, and biosynthetic activity. Interestingly, we recently established that both pharmacological inhibition of FAS activity and silencing of FAS gene expression specifically suppress Her-2/neu oncoprotein expression and tyrosine-kinase activity in breast and ovarian Her-2/neu overexpressors. Unraveling the functional organization of this novel bi-directional molecular connection between Her-2/neu and FAS-dependent neoplastic lipogenesis is a major challenge that the field is only beginning to take on. Considering that Her-2/neu overexpression correlates with increased expression of the hypoxia inducible factor-1α (HIF-1α), which, in a mitogen-activated protein kinase (MAPK)-dependent manner, plays a key role in the expression of several genes including cytokines such as vascular endothelial growth factor (VEGF), we hypothesized that FAS blockade should result in a concomitant down-regulation of VEGF. Unexpectedly, the specific inhibition of the de novo fatty acid synthesis with the small-molecule inhibitor of FAS activity C75 resulted in a dramatic dose-dependent enhancement (up to 500{\%} increase) of VEGF secretion in Her-2/neu-overexpressing SK-Br3, BT-474, and SKOV3 cancer cells. Concurrently, FAS blockade drastically activated MARK and promoted further a prominent accumulation of HIF-1α in Her-2/neu overexpressors. Moreover, U0126-induced inhibition of MAPK activity completely abolished C75-induced up-regulation of HIF-1α expression and VEGF secretion, whereas it did not modulate C75-induced down-regulation of Her-2/neu oncogene. Importantly, RNA interference (RNAi)-mediated silencing of the FAS gene recapitulated C75's effects by up-regulating VEGF secretion, MAPK activation and HIF-1α expression. Therefore, it appears that perturbation of cancer-associated endogenous fatty metabolism triggers a {"}hypoxia-like{"} (oxygen-independent) condition that actively rescues Her-2/neu-dependent MARK → HIP-1α → VEGF cascade. It is tempting to suggest that an intact FAS-catalyzed endogenous fatty acid metabolism is a necessary metabolic adaptation to support the enhanced ability of Her-2/neu-overexpressing cancer cells to survive cellular hypoxia in a HIF-α-dependent manner.",
keywords = "Angiogenesis, Cancer, erbB-2, Fatty acid synthase, Her-2/neu, Hypoxia, VEGF",
author = "Menendez, {Javier A.} and Luciano Vellon and Oza, {Bharvi P.} and Ruth Lupu",
year = "2005",
month = "4",
day = "1",
doi = "10.1002/jcb.20367",
language = "English (US)",
volume = "94",
pages = "857--863",
journal = "Journal of Cellular Biochemistry",
issn = "0730-2312",
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TY - JOUR

T1 - Does endogenous fatty acid metabolism allow cancer cells to sense hypoxia and mediate hypoxic vasodilatation? Characterization of a novel molecular connection between fatty acid synthase (FAS) and hypoxia-inducible factor-1α (HIF-1α)-related expression of vascular endothelial growth factor (VEGF) in cancer cells overexpressing Her-2/neu oncogene

AU - Menendez, Javier A.

AU - Vellon, Luciano

AU - Oza, Bharvi P.

AU - Lupu, Ruth

PY - 2005/4/1

Y1 - 2005/4/1

N2 - Her-2/neu (erbB-2) oncogene overexpression is associated with increased tumor progression and metastasis. Fatty acid synthase (FAS), the key lipogenic enzyme responsible for the endogenous synthesis of fatty acids, has been shown to be one of the genes regulated by Her-2/neu at the level of transcription, translation, and biosynthetic activity. Interestingly, we recently established that both pharmacological inhibition of FAS activity and silencing of FAS gene expression specifically suppress Her-2/neu oncoprotein expression and tyrosine-kinase activity in breast and ovarian Her-2/neu overexpressors. Unraveling the functional organization of this novel bi-directional molecular connection between Her-2/neu and FAS-dependent neoplastic lipogenesis is a major challenge that the field is only beginning to take on. Considering that Her-2/neu overexpression correlates with increased expression of the hypoxia inducible factor-1α (HIF-1α), which, in a mitogen-activated protein kinase (MAPK)-dependent manner, plays a key role in the expression of several genes including cytokines such as vascular endothelial growth factor (VEGF), we hypothesized that FAS blockade should result in a concomitant down-regulation of VEGF. Unexpectedly, the specific inhibition of the de novo fatty acid synthesis with the small-molecule inhibitor of FAS activity C75 resulted in a dramatic dose-dependent enhancement (up to 500% increase) of VEGF secretion in Her-2/neu-overexpressing SK-Br3, BT-474, and SKOV3 cancer cells. Concurrently, FAS blockade drastically activated MARK and promoted further a prominent accumulation of HIF-1α in Her-2/neu overexpressors. Moreover, U0126-induced inhibition of MAPK activity completely abolished C75-induced up-regulation of HIF-1α expression and VEGF secretion, whereas it did not modulate C75-induced down-regulation of Her-2/neu oncogene. Importantly, RNA interference (RNAi)-mediated silencing of the FAS gene recapitulated C75's effects by up-regulating VEGF secretion, MAPK activation and HIF-1α expression. Therefore, it appears that perturbation of cancer-associated endogenous fatty metabolism triggers a "hypoxia-like" (oxygen-independent) condition that actively rescues Her-2/neu-dependent MARK → HIP-1α → VEGF cascade. It is tempting to suggest that an intact FAS-catalyzed endogenous fatty acid metabolism is a necessary metabolic adaptation to support the enhanced ability of Her-2/neu-overexpressing cancer cells to survive cellular hypoxia in a HIF-α-dependent manner.

AB - Her-2/neu (erbB-2) oncogene overexpression is associated with increased tumor progression and metastasis. Fatty acid synthase (FAS), the key lipogenic enzyme responsible for the endogenous synthesis of fatty acids, has been shown to be one of the genes regulated by Her-2/neu at the level of transcription, translation, and biosynthetic activity. Interestingly, we recently established that both pharmacological inhibition of FAS activity and silencing of FAS gene expression specifically suppress Her-2/neu oncoprotein expression and tyrosine-kinase activity in breast and ovarian Her-2/neu overexpressors. Unraveling the functional organization of this novel bi-directional molecular connection between Her-2/neu and FAS-dependent neoplastic lipogenesis is a major challenge that the field is only beginning to take on. Considering that Her-2/neu overexpression correlates with increased expression of the hypoxia inducible factor-1α (HIF-1α), which, in a mitogen-activated protein kinase (MAPK)-dependent manner, plays a key role in the expression of several genes including cytokines such as vascular endothelial growth factor (VEGF), we hypothesized that FAS blockade should result in a concomitant down-regulation of VEGF. Unexpectedly, the specific inhibition of the de novo fatty acid synthesis with the small-molecule inhibitor of FAS activity C75 resulted in a dramatic dose-dependent enhancement (up to 500% increase) of VEGF secretion in Her-2/neu-overexpressing SK-Br3, BT-474, and SKOV3 cancer cells. Concurrently, FAS blockade drastically activated MARK and promoted further a prominent accumulation of HIF-1α in Her-2/neu overexpressors. Moreover, U0126-induced inhibition of MAPK activity completely abolished C75-induced up-regulation of HIF-1α expression and VEGF secretion, whereas it did not modulate C75-induced down-regulation of Her-2/neu oncogene. Importantly, RNA interference (RNAi)-mediated silencing of the FAS gene recapitulated C75's effects by up-regulating VEGF secretion, MAPK activation and HIF-1α expression. Therefore, it appears that perturbation of cancer-associated endogenous fatty metabolism triggers a "hypoxia-like" (oxygen-independent) condition that actively rescues Her-2/neu-dependent MARK → HIP-1α → VEGF cascade. It is tempting to suggest that an intact FAS-catalyzed endogenous fatty acid metabolism is a necessary metabolic adaptation to support the enhanced ability of Her-2/neu-overexpressing cancer cells to survive cellular hypoxia in a HIF-α-dependent manner.

KW - Angiogenesis

KW - Cancer

KW - erbB-2

KW - Fatty acid synthase

KW - Her-2/neu

KW - Hypoxia

KW - VEGF

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