Abstract
The tumor suppressor phosphatase and tensin homologue deleted from chromosome 10 (PTEN) gene is a negative regulator of the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt/PKB) signaling pathway. Overexpression of PTEN in cancer cells results in cell-cycle arrest and cell death through inhibition of PI3K. Caffeine, a xanthine analogue, is well known to enhance the cytocidal and growth-inhibitory effects of DNA-damaging agents such as radiation, UV light, and anticancer agents on tumor cells by abrogating DNA-damage checkpoints through inhibition of ataxia-telangiectasia-mutated (ATM), and ATM and Rad3-related (ATR) kinase activity. In this study, we demonstrate that treatment with a combination of adenovirus-mediated transfer of PTEN (Ad-PTEN) and caffeine synergistically suppressed cell growth and induced apoptosis in colorectal cancer cells but not in normal colorectal fibroblast cells. This synergistic effect was induced through abrogation of G(2)/M arrest, downregulation of the Akt pathway, and modulation of the p44/42MAPK pathway. Thus, combined treatment with Ad-PTEN and caffeine is a potential therapy for colorectal cancer.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenoviridae / genetics*
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Apoptosis / drug effects
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Caffeine / pharmacology*
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Cell Division / drug effects
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Colon / cytology
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Colon / drug effects
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Colorectal Neoplasms / drug therapy
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Colorectal Neoplasms / pathology
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Colorectal Neoplasms / radiotherapy
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Colorectal Neoplasms / therapy*
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Drug Synergism
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Fibroblasts / cytology
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Fibroblasts / drug effects
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G2 Phase / drug effects
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G2 Phase / genetics
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Genetic Therapy / methods*
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Humans
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MAP Kinase Signaling System / drug effects
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Male
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Mitosis / drug effects
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Mitosis / genetics
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PTEN Phosphohydrolase
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Protein Serine-Threonine Kinases / drug effects
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Protein Tyrosine Phosphatases / genetics*
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Protein Tyrosine Phosphatases / pharmacology
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Proto-Oncogene Proteins / drug effects
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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Radiation, Ionizing
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Reference Values
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Signal Transduction
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Tumor Cells, Cultured
Substances
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Proto-Oncogene Proteins
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Caffeine
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AKT1 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Protein Tyrosine Phosphatases
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PTEN Phosphohydrolase
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Pten protein, rat