Barker Catherine R, McNamara Anne V, Rackstraw Stephen A, Nelson David E, White Mike R, Watson Alastair J M, Jenkins John R
The Henry Wellcome Laboratory of Molecular and Cellular Gastroenterology, Division of Gastroenterology, School of Clinical Sciences, University of Liverpool, Crown Street, Liverpool L69 3BX, UK.
Nucleic Acids Res. 2006 Feb 16;34(4):1148-57. doi: 10.1093/nar/gkj516. Print 2006.
Topoisomerase II plays a crucial role during chromosome condensation and segregation in mitosis and meiosis and is a highly attractive target for chemotherapeutic agents. We have identified previously topoisomerase II and heat shock protein 90 (Hsp90) as part of a complex. In this paper we demonstrate that drug combinations targeting these two enzymes cause a synergistic increase in apoptosis. The objective of our study was to identify the mode of cell killing and the mechanism behind the increase in topoisomerase II mediated DNA damage. Importantly we demonstrate that Hsp90 inhibition results in an increased topoiosmerase II activity but not degradation of topoisomerase II and it is this, in the presence of a topoisomerase II poison that causes the increase in cell death. Our results suggest a novel mechanism of action where the inhibition of Hsp90 disrupts the Hsp90-topoisomerase II interaction leading to an increase in and activation of unbound topoisomerase II, which, in the presence of a topoisomerase II poison leads to the formation of an increased number of cleavable complexes ultimately resulting in rise in DNA damage and a subsequent increase cell death.
拓扑异构酶II在有丝分裂和减数分裂过程中的染色体浓缩和分离中起着关键作用，是化疗药物极具吸引力的靶点。我们之前已确定拓扑异构酶II和热休克蛋白90（Hsp90）是一个复合物的组成部分。在本文中，我们证明靶向这两种酶的药物组合会导致细胞凋亡协同增加。我们研究的目的是确定细胞杀伤模式以及拓扑异构酶II介导的DNA损伤增加背后的机制。重要的是，我们证明Hsp90抑制导致拓扑异构酶II活性增加，但不会导致拓扑异构酶II降解，正是在存在拓扑异构酶II毒物的情况下，这会导致细胞死亡增加。我们的结果提示了一种新的作用机制，即Hsp90抑制会破坏Hsp90 - 拓扑异构酶II相互作用，导致未结合的拓扑异构酶II增加并激活，在存在拓扑异构酶II毒物的情况下，这会导致形成更多可切割复合物，最终导致DNA损伤增加和随后细胞死亡增加。
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