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


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2016-12-20

AUTHORS

Kelly J. Higby, Melissa M. Bischak, Christina A. Campbell, Rebecca G. Anderson, Sarah A. Broskin, Lauren E. Foltz, Jarrett A. Koper, Audrey C. Nickle, Karen K. Resendes

ABSTRACT

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. More... »

PAGES

393-405

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s10495-016-1338-y

DOI

http://dx.doi.org/10.1007/s10495-016-1338-y

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1038714945

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/28000054


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37 schema:description 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.
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45 Ca2
46 Crm1-induced nuclear export
47 NPC permeability
48 Ran
49 Ran gradient
50 ability
51 accumulation
52 accumulation of topoisomerase
53 action
54 activation
55 alterations
56 apoptosis
57 calcium
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59 camptothecin
60 caspase 9 activation
61 caspase-independent increase
62 cause
63 cell death progress
64 cellular calcium
65 chelator BAPTA-AM
66 chemotherapy
67 combination chemotherapy
68 combination treatment
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70 complexes
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72 death progresses
73 dependent manner
74 disruption
75 disrupts Ran
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77 door
78 drug resistance
79 early caspase-independent increase
80 effect
81 essential component
82 export
83 general effect
84 gradient
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86 inhibitors
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88 manner
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91 nuclear accumulation
92 nuclear export
93 nuclear pore complex
94 nuclear pore permeability
95 nuclear topoisomerase
96 nuclear transport
97 nucleus
98 p53
99 permeability
100 pore complex
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102 potential combination chemotherapies
103 presence
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105 protein
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111 suppressor
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113 therapeutics
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