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Nonredundant antioxidant defense by multiple two-cysteine peroxiredoxins in human prostate cancer cells.

ABSTRACT: BACKGROUND: Peroxiredoxins (Prxs) are antioxidant enzymes expressed by most free-living organisms, often in multiple isoforms. Because mammalian Prxs have not been experimentally deleted or inhibited, it is not known how much they contribute to antioxidant defense, nor whether the multiple isoforms afford redundant or additive protection. MATERIALS AND METHODS: Expression of the four members of the 2-Cys family of human Prxs was tested in human tumor cell lines. Monospecific antibodies were developed and used to monitor the extent and specificity of inhibition of expression of each isoform in prostate cancer cells stably transfected with antisense constructs. RESULTS: Seventeen tumor lines transcribed genes for all four human Prxs. Prostate cancer cells coexpressed each isoform at the protein level. Stable transfection with antisense allowed partial, selective suppression of Prx 1, 2, 3, or 4. Prostate cancer cells were rendered more sensitive to hydrogen peroxide or an organic hydroperoxide when Prx 1, 2, or 3 but not 4 was partially suppressed, bringing them into the range of sensitivity of mouse cells. The effect of partially suppressing a single Prx was comparable to that of depleting glutathione. In contrast, sensitization to adriamycin, an antitumor agent with a redox-active quinone, followed the partial suppression of Prxs 1, 2, or 4 but not 3. Individual suppression of Prxs 1-4 had no effect on sensitivity of the cells to reactive nitrogen intermediates, tumor necrosis factor (TNF), paclitaxel (Taxol), or etoposide. CONCLUSIONS: The 2-Cys Prxs act in a mutually nonredundant and sometimes stress-specific fashion to protect human cells from oxidant injury. The substantial resistance of human cells to hydroperoxides may result in part from the additive action of multiple Prxs.

SUBMITTER: Shen C

PROVIDER: S-EPMC2039972 | biostudies-other | 2002 Feb

REPOSITORIES: biostudies-other

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Nonredundant antioxidant defense by multiple two-cysteine peroxiredoxins in human prostate cancer cells.

Shen Chuanlu C Nathan Carl C

Molecular medicine (Cambridge, Mass.) 20020201 2

<h4>Background</h4>Peroxiredoxins (Prxs) are antioxidant enzymes expressed by most free-living organisms, often in multiple isoforms. Because mammalian Prxs have not been experimentally deleted or inhibited, it is not known how much they contribute to antioxidant defense, nor whether the multiple isoforms afford redundant or additive protection.<h4>Materials and methods</h4>Expression of the four members of the 2-Cys family of human Prxs was tested in human tumor cell lines. Monospecific antibod ...[more]

PMID: 12080185

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Project description:The molecular mechanisms whereby placental growth factor (PlGF) mediates its effects in nonproliferative diabetic retinopathy (DR) are unknown. To better understand the role of PlGF in DR, we used tandem mass tags (TMT)-labeled quantitative proteomics to human retinal endothelial cells (HRECs), treated anti-PlGF antibody, and PBS as a control. Functional annotation and pathway enrichments were performed, which suggested that the differentially expressed proteins (DEPs) were involved in key metabolic processes, protein binding, and membrane, pentose phosphate pathway (PPP) and adherens junction. We conducted integrated gene profiles of our previously published transcriptomic data to the TMT-labeled proteomics data. The results showed the sixty genes were found to be changed at the proteome level. The functional annotation conducted for the sixty proteins suggested that 58.3% of proteins were involved in PPP, 25% of proteins were in interleukin-12 singling and 16.7% of proteins were involved in glycolysis and gluconeogenesis pathway. Mass spectrometry results were validated by transendothelial electrical resistance measurement by an electrical cell-impedance sensing (ECIS) and western blot analysis of VE-cadherin, G6PD. These findings suggest that the PPP proteins and antioxidants may act as a downstream target of PlGF and may play a decisive role in HREC biological functions in DR. SIGNIFICANCE: PlGF (Placental growth factor) is known to play a pivotal role in pathological angiogenesis and inflammation by stimulating endothelial cell migration and by recruiting pericytes and inflammatory cells such as microglia and macrophages. Despite the well-defined pathophysiological roles of PlGF, the underlying molecular and cellular mechanisms are not completely understood, especially the exact relationships between biochemical events and molecular pathways regulated by PlGF, whose inhibition exhibits a protective role in DR. This study provides new insights into protein expression patterns and enables the identification of many attractive candidates for investigation of PPP pathway role in the activation of the antioxidant defense system in DR. Our findings suggest that the PPP proteins and antioxidants (PRDX6, HMOX1, NQO1 and YES1) may act as downstream targets of PlGF and may play a decisive role in HREC biological functions in DR.

Dataset Information

Nonredundant antioxidant defense by multiple two-cysteine peroxiredoxins in human prostate cancer cells.

Publications

Nonredundant antioxidant defense by multiple two-cysteine peroxiredoxins in human prostate cancer cells.

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