5-Flurouracil disrupts nuclear export and nuclear pore permeability in a calcium dependent manner

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• 作者：Kelly J. Higby ; Melissa M. Bischak ; Christina A. Campbell ; Rebecca G. Anderson…
• 关键词：5 ; Flurouracil ; Nuclear transport ; Ran ; Calcium ; Topoisomerase
• 刊名：Apoptosis
• 出版年：2017
• 出版时间：March 2017
• 年：2017
• 卷：22
• 期：3
• 页码：393-405
• 全文大小：
• 刊物类别：Medicine
• 刊物主题：Cancer Research; Cell Biology; Oncology; Biochemistry, general; Virology;
• 出版者：Springer US
• ISSN：1573-675X
• 卷排序：22

文摘

Regulation of nuclear transport is an essential component of apoptosis. As chemotherapy induced cell death progresses, nuclear transport and the nuclear pore complex (NPC) are slowly disrupted and dismantled. 5-Fluorouracil (5-FU) and the camptothecin derivatives irinotecan and topotecan, are linked to altered nuclear transport of specific proteins; however, their general effects on the NPC and transport during apoptosis have not been characterized. We demonstrate that 5-FU, but not topotecan, increases NPC permeability, and disrupts Ran-mediated nuclear transport before the disruption of the NPC. This increased permeability is dependent on increased cellular calcium, as the Ca2+ chelator BAPTA-AM, abolishes the effect. Furthermore, increased calcium alone was sufficient to disrupt the Ran gradient. Combination treatments of 5-FU with topotecan or irinotecan, similarly disrupted nuclear transport before disassembly of the NPC. In both single and combination treatments nuclear transport was disrupted before caspase 9 activation, indicating that 5-FU induces an early caspase-independent increase in NPC permeability and alteration of nuclear transport. Because Crm1-mediated nuclear export of tumor suppressors is linked to drug resistance we also examined the effect of 5-FU on the nuclear export of a specific target, topoisomerase. 5-FU treatment led to accumulation of topoisomerase in the nucleus and recovered the loss nuclear topoisomerase induced by irinotecan or topotecan, a known cause of drug resistance. Furthermore, 5-FU retains its ability to cause nuclear accumulation of p53 in the presence of irinotecan or topotecan. Our results reveal a new mechanism of action for these therapeutics during apoptosis, opening the door to other potential combination chemotherapies that employ 5-FU as a calcium mediated inhibitor of Crm1-induced nuclear export of tumor suppressors.