1. T-LAK cell-originated protein kinase (TOPK) enhances androgen receptor splice variant (ARv7) and drives androgen-independent growth in prostate cancer.
- Author
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Alhawas L, Amin KS, Salla B, and Banerjee PP
- Subjects
- Alternative Splicing, Androgen Antagonists pharmacology, Androgen Antagonists therapeutic use, Androgens metabolism, Antineoplastic Agents, Hormonal pharmacology, Antineoplastic Agents, Hormonal therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Biomarkers, Tumor analysis, Biomarkers, Tumor antagonists & inhibitors, Biomarkers, Tumor metabolism, Cell Line, Tumor, Disease-Free Survival, Drug Resistance, Neoplasm drug effects, Drug Resistance, Neoplasm genetics, Humans, Inhibitory Concentration 50, Male, Mitogen-Activated Protein Kinase Kinases analysis, Mitogen-Activated Protein Kinase Kinases antagonists & inhibitors, Neoplasm Recurrence, Local epidemiology, Neoplasm Recurrence, Local prevention & control, Prognosis, Prostate pathology, Prostatic Neoplasms, Castration-Resistant drug therapy, Prostatic Neoplasms, Castration-Resistant mortality, Prostatic Neoplasms, Castration-Resistant pathology, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Quinolones pharmacology, Quinolones therapeutic use, Receptors, Androgen metabolism, Signal Transduction drug effects, Signal Transduction genetics, Thiophenes pharmacology, Thiophenes therapeutic use, Transcriptional Activation drug effects, Antineoplastic Combined Chemotherapy Protocols pharmacology, Mitogen-Activated Protein Kinase Kinases metabolism, Neoplasm Recurrence, Local genetics, Prostatic Neoplasms, Castration-Resistant genetics, Receptors, Androgen genetics
- 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., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Published
- 2021
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