Abstract
Docetaxel is used as a standard treatment in patients with metastatic castration-resistant prostate cancer. However, a large subset of patients develops resistance. Understanding resistance mechanisms, which are largely unknown, will allow identification of predictive biomarkers and therapeutic targets. We established resistant IGR-CaP1 prostate cancer cell lines for different doses of Docetaxel. We investigated gene expression profiles by microarray analyses in these cell lines and generated a signature of 99 highly differentially expressed genes potentially implicated in chemoresistance. We focused on the role of the cell cycle regulator LZTS1, which was under-expressed in the Docetaxel-resistant cell lines, its inhibition resulting from the promoter methylation. Knockdown of LZTS1 in parental cells with siRNA showed that LZTS1 plays a role in the acquisition of the resistant phenotype. Furthermore, we observed that targeting CDC25C, a partner of LZTS1, with the NSC663284 inhibitor specifically killed the Docetaxel-resistant cells. To further investigate the role of CDC25C, we used inhibitors of the mitotic kinases that regulate CDC25C. Inhibition of CHEK1 and PLK1 induced growth arrest and cell death in the resistant cells. Our findings identify an important role of LZTS1 through its regulation of CDC25C in Docetaxel resistance in prostate cancer and suggest that CDC25C, or the mitotic kinases CHEK1 and PLK1, could be efficient therapeutic targets to overcome Docetaxel resistance.
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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Cell Cycle Proteins / antagonists & inhibitors
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Cell Cycle Proteins / metabolism
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Cell Line, Tumor
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Checkpoint Kinase 1
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DNA-Binding Proteins / deficiency*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Docetaxel
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Drug Resistance, Neoplasm
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Gene Knockdown Techniques
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Humans
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Male
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Molecular Targeted Therapy
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Polo-Like Kinase 1
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Prostatic Neoplasms, Castration-Resistant / drug therapy*
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Prostatic Neoplasms, Castration-Resistant / metabolism*
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Prostatic Neoplasms, Castration-Resistant / pathology
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Protein Kinases / genetics
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Protein Kinases / metabolism*
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins / antagonists & inhibitors
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Proto-Oncogene Proteins / metabolism
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RNA, Small Interfering / administration & dosage
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RNA, Small Interfering / genetics
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Taxoids / pharmacology*
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Tissue Array Analysis
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Transcriptome
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Transfection
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Tumor Suppressor Proteins / deficiency*
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
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cdc25 Phosphatases / antagonists & inhibitors*
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cdc25 Phosphatases / metabolism
Substances
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Antineoplastic Agents
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Cell Cycle Proteins
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DNA-Binding Proteins
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LZTS1 protein, human
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Proto-Oncogene Proteins
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RNA, Small Interfering
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Taxoids
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Tumor Suppressor Proteins
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Docetaxel
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Protein Kinases
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CHEK1 protein, human
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Checkpoint Kinase 1
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Protein Serine-Threonine Kinases
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CDC25C protein, human
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cdc25 Phosphatases