Abstract
Cisplatin is one of the most commonly used drugs in the treatment of gastric cancer. However, drug resistance is a major obstacle for effective treatment and originates in multiple mechanisms such as enhanced DNA repair and anti-apoptosis. Our previous results demonstrated that XRCC1 was a key regulator of cisplatin induced DNA damage and apoptosis. TXNL1, a member of the thioredoxin family, negatively regulated the expression of XRCC1 via the ubiquitin-proteasome pathway. Here, we investigated the role of TXNL1 in the apoptosis induced by cisplatin. Our data showed that the expression of TXNL1 in the cisplatin resistant gastric cancer cell lines BGC823/DDP and SGC7901/DDP cells was significantly lower compared with the cisplatin sensitive cell lines BGC823 and SGC7901. Inhibition of the expression of TXNL1 in BGC823 and SGC7901 cells led to increased resistance to cisplatin induced apoptosis and cell death detected by Tunel and clonogenic assay, respectively. In contrast, over expression of TXNL1 in BGC823/DDP and SGC7901/DDP cells lead to higher cisplatin induced apoptosis and cell death. Moreover, our results demonstrated that the mechanism of TXNL1 regulating cisplatin-induced apoptosis was closely associated with Bcl-2 mediated mitochondria apoptosis pathway. In conclusion, these findings suggest that TXNL1 was a feasible modulator and potential chemotherapeutic target for the cisplatin resistant phenotype of human gastric cancer cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects*
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Biomarkers / metabolism
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Cell Line, Tumor
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Cisplatin / pharmacology*
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Colony-Forming Units Assay
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DNA-Binding Proteins / agonists
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Drug Resistance, Neoplasm*
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Mitochondria / drug effects
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Mitochondria / metabolism
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Mitochondria / pathology
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Neoplasm Proteins / agonists
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism*
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Osmolar Concentration
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Proto-Oncogene Proteins c-bcl-2 / agonists
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Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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RNA Interference
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RNA, Small Interfering
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Recombinant Fusion Proteins / chemistry
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Recombinant Fusion Proteins / metabolism
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Signal Transduction / drug effects
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Stomach Neoplasms / drug therapy*
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Stomach Neoplasms / metabolism
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Stomach Neoplasms / pathology
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Thioredoxins / antagonists & inhibitors
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Thioredoxins / genetics
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Thioredoxins / metabolism*
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X-ray Repair Cross Complementing Protein 1
Substances
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Antineoplastic Agents
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BCL2 protein, human
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Biomarkers
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DNA-Binding Proteins
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Neoplasm Proteins
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Proto-Oncogene Proteins c-bcl-2
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RNA, Small Interfering
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Recombinant Fusion Proteins
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TXNL1 protein, human
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X-ray Repair Cross Complementing Protein 1
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XRCC1 protein, human
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Thioredoxins
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Cisplatin