Abstract
Despite impressive advances in the treatment of prostate cancer with various efficacious inhibitors along the androgen/androgen receptor axis, eventual development of incurable metastatic Castration-Resistant Prostate Cancer (mCRPC) is inevitable and remains a major clinical challenge. Constitutively active androgen receptor (AR) spliced variants have emerged as primary means of resistance to anti-androgens and androgen synthesis inhibitors. The alternatively spliced AR variant, ARv7, has attracted significant interest due to its constitutively active status in CRPC that drives androgen-independence. Factors that are involved in regulating ARv7 levels in CRPC are not clearly known. We recently demonstrated that a protein kinase, T-LAK cell-originated protein kinase (TOPK) level correlates with the aggressiveness of prostate cancer and its invasive behavior. In this study, we investigated whether TOPK plays a role in driving androgen-independence in prostate cancer cells. Our data demonstrate that TOPK overexpression in androgen-dependent LNCaP and VCaP induces ARv7 and drives androgen-independent growth. On the other hand, pharmacological inhibition of TOPK in androgen-independent LNCaP95 and 22Rv1 represses AR transactivation, and AR stability. In summary, this study illustrates a direct role of TOPK in regulating ARv7 and driving androgen-independence in prostate cancer cells.
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Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alternative Splicing
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Androgen Antagonists / pharmacology
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Androgen Antagonists / therapeutic use
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Androgens / metabolism
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Antineoplastic Agents, Hormonal / pharmacology
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Antineoplastic Agents, Hormonal / therapeutic use
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Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use
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Biomarkers, Tumor / analysis
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Biomarkers, Tumor / antagonists & inhibitors
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Biomarkers, Tumor / metabolism
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Cell Line, Tumor
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Disease-Free Survival
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Drug Resistance, Neoplasm / drug effects
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Drug Resistance, Neoplasm / genetics
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Humans
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Inhibitory Concentration 50
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Male
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Mitogen-Activated Protein Kinase Kinases / analysis
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Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinase Kinases / metabolism*
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Neoplasm Recurrence, Local / epidemiology
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Neoplasm Recurrence, Local / genetics*
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Neoplasm Recurrence, Local / prevention & control
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Prognosis
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Prostate / pathology
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Prostatic Neoplasms, Castration-Resistant / drug therapy
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Prostatic Neoplasms, Castration-Resistant / genetics*
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Prostatic Neoplasms, Castration-Resistant / mortality
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Prostatic Neoplasms, Castration-Resistant / pathology
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Protein Kinase Inhibitors / pharmacology
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Protein Kinase Inhibitors / therapeutic use
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Quinolones / pharmacology
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Quinolones / therapeutic use
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Receptors, Androgen / genetics*
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Receptors, Androgen / metabolism
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Thiophenes / pharmacology
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Thiophenes / therapeutic use
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Transcriptional Activation / drug effects
Substances
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AR protein, human
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Androgen Antagonists
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Androgens
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Antineoplastic Agents, Hormonal
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Biomarkers, Tumor
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OTS514
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Protein Kinase Inhibitors
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Quinolones
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Receptors, Androgen
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Thiophenes
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Mitogen-Activated Protein Kinase Kinases
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PDZ-binding kinase