Neoplasma Vol.53, p.144-149, 2006
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| Title: The regulation of human adrenomedullin (AM) and tumor necrosis
factor alpha (TNF-alpha) receptors on human epithelial carcinoma (HeLa) cells. The role of AM secretion in tumor cell sensitivity
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| Author: D., DRIMAL
; J., DRIMAL
; J., DRIMAL JR
; |
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Abstract: The cytostatic cytokine tumor necrosis factor-alpha (TNF-alpha)
and proliferative hormone adrenomedullin (AM) are abundantly
expressed in human tumors. However, little is known about mechanism
(s) through which TNF-alpha and AM exert their
regulatory effects, especially in the regulation of proliferative
activity in malignant cells. Also the role played by TNF-alpha in
pathogenesis and treatment of cancer (targeted cancer therapy)
remains less understood. The purpose of this study was
therefore to characterize the significance of TNF-alpha induced
apoptosis with down-regulation of plasma-membrane TNF-alpha
receptors and up-regulation of AM receptors with increased
production of human AM mRNA, i.e. mechanisms that subsequently
control aberrant cellular proliferation in malignant cells.
Cytotoxicity, and the whole cell ligand binding assays for
TNF-alpha and AM receptors, and RIA-assays of AM production were
accomplished in control experiments using pharmacologically
pretreated HeLa cells. AMincreased proliferation of HeLa cells
andAMantagonist (Ala6,21)AM(22-52) significantly
antagonized this increase. TNF-alpha inhibitor of cell growth
actinomycin-D significantly increased cytotoxicity of TNF-alpha in
HeLa cells. Hypoxia increased TNF-alpha production and increased
surface-membrane [125I]AM binding. Tumor promotor
PMA and histamine down-regulated specific binding of [125I]TNF-
alpha on HeLa cells. Mitogenic peptide endothelin-1 increased
and specific ET-1 antagonist BQ123 and significantly reduced AM
binding. Production of AM in HeLa cells markedly
increased after exposure to hypoxia >ET-1 >PMA. BAY11-7082 at
concentrations that inhibited IęB phosphorylation
and thus nuclear translocation and surface membrane TNF-alpha
expression increased AM specific binding. Pretreatment of
cells inhibitor of HMGCoA reductase inhibitor VULM1457
significantly increased the total number of specific [125I]AM
binding sites on HeLa cells. These results suggest relative and
contradictory TNF-alpha and AM surface-membrane receptor
signaling in HeLa cells and findings reveal a novel proliferative
mechanisms that controlAMproduction and thus oncogenic
signaling in cells. This implies that several putative inhibitors
of TNF-alpha and AM signaling may be considered in oncology
for treatment of tumors otherwise nonresponding to cytostatic
therapy.
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| Keywords: TNF-alpha, adrenomedullin, receptors, AM production, proliferation,
HeLa, epithelial carcinoma cells, cells in
culture
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| Year: 2006, Volume: 53, Issue: |
Page From: 144, Page To: 149 |
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