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.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Mitogen-Activated Protein Kinase Kinases/metabolism , Neoplasm Recurrence, Local/genetics , Prostatic Neoplasms, Castration-Resistant/genetics , Receptors, Androgen/genetics , 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 effectsABSTRACT
Malignant peripheral nerve sheath tumor (MPNST) is a rare, aggressive soft-tissue sarcoma with a poor prognosis and is insensitive to immune checkpoint blockade (ICB) therapy. Loss-of-function of the histone modifying polycomb repressive complex 2 (PRC2) components, EED or SUZ12, is one of the main mechanisms of malignant transformation. In a murine model of MPNST, PRC2-loss tumors have an "immune desert" phenotype and intratumoral (IT) delivery immunogenic modified vaccinia virus Ankara (MVA) sensitized the PRC2-loss tumors to ICB. Here we show that IT MQ833, a second-generation recombinant modified vaccinia virus Ankara virus, results in neutrophil recruitment and activation and neutrophil-dependent tumor killing in the MPNST model. MQ833 was engineered by deleting three viral immune evasion genes, E5R, E3L, and WR199, and expressing three transgenes, including the two membrane-bound Flt3L and OX40L, and IL-12 with an extracellular matrix anchoring signal. Furthermore, we explored strategies to enhance anti-tumor effects of MQ833 by co-administration of granulocyte colony-stimulating factor (G-CSF).