Abstract
Gastric cancer is the most common type of tumor in developing countries and the fourth most frequently diagnosed cancer worldwide. Here, we demonstrated the apoptotic effects of GL-V9 on several human gastric cancer cells and selected MGC-803 cells to uncover the underlying mechanism. GL-V9 elevated Bax/Bcl-2 ratio, abated mitochondrial membrane potential and triggered the onset of apoptotic execution in MGC-803 cells. Our research revealed that CHOP silencing could not inhibit apoptosis, neither could it block Ca2+ release, suggesting that GL-V9-induced apoptosis was independent of CHOP. Furthermore, GL-V9 increased mitochondrial Ca2+ uptake through 1,4,5-triphosphate (IP3) receptor via the activation of phospholipase C-γ1 and the translocation of phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase from nucleus to endoplasmic reticulum. Moreover, in-vivo studies indicated that GL-V9 exhibited significant MGC-803 xenografts regression in nude mice with low systemic toxicity. In conclusion, GL-V9 could induce apoptosis in gastric cancer cells, and would be a promising therapeutical agent against gastric cancer.
Keywords:
Apoptosis; Ca(2+) release; GL-V9; Gastric cancer.
Copyright © 2017 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Active Transport, Cell Nucleus / drug effects
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Active Transport, Cell Nucleus / physiology
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Animals
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Apoptosis / drug effects*
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Apoptosis / genetics*
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Calcium / metabolism
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Cell Line, Tumor
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Endoplasmic Reticulum / metabolism
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Enzyme Activation
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Female
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Flavonoids / pharmacology*
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Humans
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Inositol 1,4,5-Trisphosphate Receptors / metabolism
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Membrane Potential, Mitochondrial / drug effects
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Membrane Potential, Mitochondrial / physiology
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Mitochondria / physiology
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PTEN Phosphohydrolase / metabolism*
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Phospholipase C gamma / metabolism*
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Phosphoric Monoester Hydrolases / metabolism*
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Stomach Neoplasms / genetics
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Stomach Neoplasms / pathology*
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Transcription Factor CHOP / genetics
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Xenograft Model Antitumor Assays
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bcl-2-Associated X Protein / metabolism
Substances
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5-hydroxy-8-methoxy-2-phenyl-7-(4-(pyrrolidin-1-yl)butoxy)4H-chromen-4-one
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BAX protein, human
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DDIT3 protein, human
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Flavonoids
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Inositol 1,4,5-Trisphosphate Receptors
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Proto-Oncogene Proteins c-bcl-2
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bcl-2-Associated X Protein
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Transcription Factor CHOP
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Phosphoric Monoester Hydrolases
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PTEN Phosphohydrolase
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PTEN protein, human
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Phospholipase C gamma
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Calcium