Abstract
5-Fluorouracil (5-FU) is an essential component of anticancer chemotherapy against gastric cancer. However, the response rate of single drug is still limited. The ubiquitin ligase Cbl-b is a negative regulator of growth factor receptor signaling and is involved in the suppression of cancer cell proliferation. However, whether Cbl-b could affect 5-FU sensitivity remains unclear. The present study showed that Cbl-b knockdown caused higher proliferation concomitant with the decrease of apoptosis induced by 5-FU treatment in gastric cancer cell. Further mechanism investigation demonstrated that Cbl-b knockdown caused significant increase of phosphorylation of EGFR, ERK and Akt, decrease of mitochondrial membrane potential, and increase of expression ratio of Bcl-2/Bax. These results suggest that Cbl-b enhances sensitivity to 5-FU via EGFR- and mitochondria-mediated pathways in gastric cancer cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / antagonists & inhibitors
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism*
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Apoptosis / drug effects*
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Cell Line, Tumor
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Cell Proliferation / drug effects
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ErbB Receptors / antagonists & inhibitors
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ErbB Receptors / metabolism*
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Fluorouracil / toxicity*
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Humans
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Mitochondria / metabolism*
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Phosphorylation / drug effects
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Proto-Oncogene Proteins c-akt / metabolism
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Proto-Oncogene Proteins c-cbl / antagonists & inhibitors
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Proto-Oncogene Proteins c-cbl / genetics
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Proto-Oncogene Proteins c-cbl / metabolism*
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RNA Interference
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RNA, Small Interfering / metabolism
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Signal Transduction / drug effects
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Stomach Neoplasms / metabolism
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Stomach Neoplasms / pathology
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bcl-2-Associated X Protein / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Proto-Oncogene Proteins c-bcl-2
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RNA, Small Interfering
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bcl-2-Associated X Protein
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CBLB protein, human
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Proto-Oncogene Proteins c-cbl
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EGFR protein, human
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ErbB Receptors
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Proto-Oncogene Proteins c-akt
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Extracellular Signal-Regulated MAP Kinases
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Fluorouracil