Schaefer-Klein J L, Murphy Stephen J, Johnson Sarah H, Vasmatzis George, Kovtun Irina V
Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.
Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.
PLoS One. 2015 Nov 11;10(11):e0142327. doi: 10.1371/journal.pone.0142327. eCollection 2015.
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.
TOP2A的过表达与前列腺癌患者全身进展风险相关，并且在激素抵抗病例中发现TOP2A水平更高。为了阐明高水平TOP2A促进肿瘤进展的机制，我们构建了TOP2A过表达的前列腺癌细胞系。我们发现，TOP2A通过诱导有助于形成更具侵袭性表型的基因发生染色体重排来促进肿瘤侵袭性。由于雄激素受体网络的激活，单独的抗雄激素治疗在杀死TOP2A过表达细胞方面无效。TOP2A毒素在病程早期更有效地杀死肿瘤细胞，而在后期与抗雄激素治疗联合使用时能带来更大益处。从机制上讲，我们发现TOP2A通过促进雄激素反应基因的转录来增强雄激素信号传导，从而促进肿瘤细胞生长。这些研究揭示了TOP2A与雄激素受体信号通路之间的关系，该关系有助于前列腺癌进展并赋予对治疗的敏感性。
