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Human Golgi antiapoptotic protein modulates intracellular calcium fluxes.

ABSTRACT: Golgi antiapoptotic protein (GAAP) is a novel regulator of cell death that is highly conserved in eukaryotes and present in some poxviruses, but its molecular mechanism is unknown. Given that alterations in intracellular Ca(2+) homeostasis play an important role in determining cell sensitivity to apoptosis, we investigated if GAAP affected Ca(2+) signaling. Overexpression of human (h)-GAAP suppressed staurosporine-induced, capacitative Ca(2+) influx from the extracellular space. In addition, it reduced histamine-induced Ca(2+) release from intracellular stores through inositol trisphosphate receptors. h-GAAP not only decreased the magnitude of the histamine-induced Ca(2+) fluxes from stores to cytosol and mitochondrial matrices, but it also reduced the induction and frequency of oscillatory changes in cytosolic Ca(2+). Overexpression of h-GAAP lowered the Ca(2+) content of the intracellular stores and decreased the efficacy of IP(3), providing possible explanations for the observed results. Opposite effects were obtained when h-GAAP was knocked down by siRNA. Thus, our data demonstrate that h-GAAP modulates intracellular Ca(2+) fluxes induced by both physiological and apoptotic stimuli.

SUBMITTER: de Mattia F

PROVIDER: S-EPMC2777924 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature

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Human Golgi antiapoptotic protein modulates intracellular calcium fluxes.

de Mattia Fabrizio F Gubser Caroline C van Dommelen Michiel M T MM Visch Henk-Jan HJ Distelmaier Felix F Postigo Antonio A Luyten Tomas T Parys Jan B JB de Smedt Humbert H Smith Geoffey L GL Willems Peter H G M PH van Kuppeveld Frank J M FJ

Molecular biology of the cell 20090624 16

Golgi antiapoptotic protein (GAAP) is a novel regulator of cell death that is highly conserved in eukaryotes and present in some poxviruses, but its molecular mechanism is unknown. Given that alterations in intracellular Ca(2+) homeostasis play an important role in determining cell sensitivity to apoptosis, we investigated if GAAP affected Ca(2+) signaling. Overexpression of human (h)-GAAP suppressed staurosporine-induced, capacitative Ca(2+) influx from the extracellular space. In addition, it ...[more]

PMID: 19553469

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Project description:BackgroundSome retrospective and in vitro studies suggest that general anesthetics influence breast cancer recurrence and metastasis. We compared the effects of general anesthetics sevoflurane versus propofol on breast cancer cell survival, proliferation and invasion in vitro. The investigation focused on effects in intracellular Ca2+ homeostasis as a mechanism for general anesthetic-mediated effects on breast cancer cell survival and metastasis.MethodsEstrogen receptor-positive (MCF7) and estrogen receptor-negative (MDA-MB-436) human breast cancer cell lines along with normal breast tissue (MCF10A) were used. Cells were exposed to sevoflurane or propofol at clinically relevant and extreme doses and durations for dose- and time-dependence studies. Cell survival, proliferation and migration following anesthetic exposure were assessed. Intracellular and extracellular Ca2+ concentrations were modulated using Ca2+ chelation and a TRPV1 Ca2+ channel antagonist to examine the role of Ca2+ in mediating anesthetic effects.ResultsSevoflurane affected breast cancer cell survival in dose-, time- and cell type-dependent manners. Sevoflurane, but not propofol, at equipotent and clinically relevant doses (2% vs. 2 μM) for 6 h significantly promoted breast cell survival in all three types of cells. Paradoxically, extreme exposure to sevoflurane (4%, 24 h) decreased survival in all three cell lines. Chelation of cytosolic Ca2+ dramatically decreased cell survival in both breast cancer lines but not control cells. Inhibition of TRPV1 receptors significantly reduced cell survival in all cell types, an effect that was partially reversed by equipotent sevoflurane but not propofol. Six-hour exposure to sevoflurane or propofol did not affect cell proliferation, metastasis or TRPV1 protein expression in any type of cell.ConclusionSevoflurane, but not propofol, at clinically relevant concentrations and durations, increased survival of breast cancer cells in vitro but had no effect on cell proliferation, migration or TRPV1 expression. Breast cancer cells require higher cytoplasmic Ca2+ levels for survival than normal breast tissue. Sevoflurane affects breast cancer cell survival via modulation of intracellular Ca2+ homeostasis.

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Human Golgi antiapoptotic protein modulates intracellular calcium fluxes.

Publications

Human Golgi antiapoptotic protein modulates intracellular calcium fluxes.

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