Abstract
The inherent resistance of tumors to DNA damage often limits the efficacy of chemotherapy. The aim of this work is to explore the potential mechanism for development of chemoresistance in gastric cancer. Our data revealed that AKT1 mRNA and protein expression were induced by doxorubicin (a chemotherapeutic agent); the doxorubicin-induced AKT1 expression and activation increased the binding of NF-kappaB on Notch1 DNA promoter and then promoted the Notch1 transcription and expression; enhanced expression of Notch1 further upregulated PTEN expression through CBF-1 binding to PTEN DNA promoter; and inhibition of AKT1 expression and activity sensitized the gastric cancer cell to doxorubicin treatment in cultured gastric cancer cell lines and xenograft nude mice gastric cancer model. Furthermore, our data demonstrated that both Notch1 and PTEN were absent or minimally expressed in gastric cancer tissue but abundant in paired normal gastric mucosa, and the expression of Notch1 correlated with that of PTEN. Together, these novel results suggested that a novel AKT1/NF-kappaB/Notch1/PTEN axis has an important role in the development of chemoresistance in gastric cancer. Notch1 has an anti-cancer role in gastric cancer.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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Apoptosis / genetics
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Base Sequence
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Cell Line, Tumor
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Doxorubicin / pharmacology
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Doxorubicin / therapeutic use
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Drug Resistance, Neoplasm* / drug effects
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Female
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Immunoglobulin J Recombination Signal Sequence-Binding Protein / metabolism
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Male
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Mice
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Mice, Nude
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Molecular Sequence Data
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NF-kappa B / metabolism*
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PTEN Phosphohydrolase / genetics
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PTEN Phosphohydrolase / metabolism*
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Promoter Regions, Genetic / genetics
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Protein Binding / drug effects
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Protein Binding / genetics
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism*
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Receptor, Notch1 / genetics
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Receptor, Notch1 / metabolism*
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Signal Transduction / drug effects
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Stomach Neoplasms / drug therapy*
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Stomach Neoplasms / genetics
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Stomach Neoplasms / metabolism*
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Stomach Neoplasms / pathology
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Transcription Factor RelA / metabolism
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Transcription, Genetic / drug effects
Substances
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Immunoglobulin J Recombination Signal Sequence-Binding Protein
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NF-kappa B
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NOTCH1 protein, human
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RBPJ protein, human
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Receptor, Notch1
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Transcription Factor RelA
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Doxorubicin
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AKT1 protein, human
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Proto-Oncogene Proteins c-akt
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PTEN Phosphohydrolase
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PTEN protein, human