Abstract
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.
Highlights
DNA topoisomerase 2 alpha (TOP2A) is an essential nuclear enzyme, required for resolution of topological stress associated with DNA replication
We hypothesized that high levels of TOP2A, beyond those normally present in cycling cells, cause persistent generation of DNA double strand breaks (DSB) which subsequently lead to genomic rearrangements associated with formation of a more aggressive phenotype (S1A Fig)
To overcome apoptosis induced by high levels of TOP2A, we first generated prostate cancer (PCa) LNCaP stable clones overexpressing CKS2 (S1B Fig), and clones with reduced level of caspase-3 (S1C Fig), a major effector caspase in apoptotic pathway [41]
Summary
DNA topoisomerase 2 alpha (TOP2A) is an essential nuclear enzyme, required for resolution of topological stress associated with DNA replication. TOP2A introduces transient double strand breaks (DSB) on DNA in an ATP-dependent fashion to allow changes in DNA topology and eliminate over-winding [1,2]. TOP2A function is crucial in many biological processes, including replication, transcription, DNA repair and chromosome structure maintenance. It is expressed at high levels in dividing cells as its level is known to be regulated through cell cycle, and it is often used as a proliferative marker [3,4]. High level of TOP2A as an indicator of more aggressive behavior and advanced stage was PLOS ONE | DOI:10.1371/journal.pone.0142327. High level of TOP2A as an indicator of more aggressive behavior and advanced stage was PLOS ONE | DOI:10.1371/journal.pone.0142327 November 11, 2015
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