Topoisomerase 2 Alpha Cooperates with Androgen Receptor to Contribute to Prostate Cancer Progression

• Published in: PloS one 2015-11, Vol.10 (11), p.e0142327-e0142327
• Main Authors: Schaefer-Klein, J L, Murphy, Stephen J, Johnson, Sarah H, Vasmatzis, George, Kovtun, Irina V
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Androgen receptors; Androgens; Antigens, Neoplasm - metabolism; Apoptosis; Cancer; Cancer therapies; Cell cycle; Cell growth; Cell Line, Tumor; Cell Movement - physiology; Cell Proliferation - physiology; Chemotherapy; Chromosome rearrangements; Deoxyribonucleic acid; Development and progression; Disease Progression; DNA; DNA Topoisomerases, Type II - metabolism; DNA-Binding Proteins - metabolism; Enzymes; Gene Expression Regulation, Neoplastic; Genes; Genomes; Health risks; Humans; Invasiveness; Male; Metastasis; Neoplasm Invasiveness - pathology; Phenotypes; Poisons; Poly-ADP-Ribose Binding Proteins; Precision medicine; Prostate cancer; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Proteins; Receptors, Androgen - metabolism; Signal transduction; Signal Transduction - physiology; Signaling; Transcription; Transcription (Genetics); Tumor cell lines; Tumor cells; Tumors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0142327

Overexpression of TOP2A is associated with risk of systemic progression in prostate cancer patients, and higher levels of TOP2A were found in hormone-resistant cases. To elucidate the mechanism by which high levels of TOP2A contribute to tumor progression we generated TOP2A overexpressing prostate cancer cell lines. We show that TOP2A promotes tumor aggressiveness by inducing chromosomal rearrangements of genes that contribute to a more invasive phenotype. Anti-androgen treatment alone was ineffective in killing TOP2A overexpressing cells due to activation of an androgen receptor network. TOP2A poisons killed tumor cells more efficiently early in the progression course, while at later stages they provided greater benefit when combined with anti-androgen therapy. Mechanistically, we find that TOP2A enhances androgen signaling by facilitating transcription of androgen responsive genes, thereby promoting tumor cell growth. These studies revealed a relationship between TOP2A and androgen receptor signaling pathway that contributes to prostate cancer progression and confers sensitivity to treatments.