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

Kelly J Higby1,2, Melissa M Bischak1,3, Christina A Campbell1,4

  • 1Department of Biology Hoyt Science Center 222, Westminster College, 319 S Market Street, New Wilmington, PA, 16172, USA.

Apoptosis : an International Journal on Programmed Cell Death
|December 22, 2016
PubMed

Insights

5-Fluorouracil (5-FU) disrupts nuclear transport and increases nuclear pore complex (NPC) permeability via calcium, independent of caspase activation. This mechanism enhances chemotherapy efficacy by retaining tumor suppressors in the nucleus.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Pharmacology

Background:

  • Nuclear transport regulation is crucial for apoptosis and is disrupted by chemotherapy.
  • The effects of 5-Fluorouracil (5-FU) and camptothecins on nuclear pore complex (NPC) function during apoptosis are not fully understood.
  • Crm1-mediated nuclear export of tumor suppressors is implicated in drug resistance.

Purpose of the Study:

  • To characterize the general effects of 5-FU, topotecan, and irinotecan on NPC and nuclear transport during apoptosis.
  • To investigate the role of calcium and caspase activation in 5-FU-induced nuclear transport alterations.
  • To examine the impact of 5-FU on the nuclear export of topoisomerase and p53, and its implications for drug resistance.

Main Methods:

  • Assessed NPC permeability and Ran-mediated nuclear transport in response to 5-FU, topotecan, and irinotecan.
  • Utilized the calcium chelator BAPTA-AM to investigate the role of cellular calcium.
  • Examined nuclear accumulation of topoisomerase and p53 following drug treatments.

Main Results:

  • 5-FU, but not topotecan, increased NPC permeability and disrupted Ran-mediated transport before NPC disassembly, dependent on increased cellular calcium.
  • Increased calcium alone disrupted the Ran gradient.
  • Combination treatments with 5-FU and camptothecins disrupted nuclear transport before NPC disassembly and caspase 9 activation, indicating an early, caspase-independent mechanism.
  • 5-FU promoted nuclear accumulation of topoisomerase, counteracting the loss induced by irinotecan/topotecan, and retained p53 nuclear accumulation in combination treatments.

Conclusions:

  • 5-FU induces an early, calcium-dependent, caspase-independent increase in NPC permeability and alters nuclear transport.
  • 5-FU enhances chemotherapy efficacy by inhibiting Crm1-mediated nuclear export of tumor suppressors like topoisomerase and p53.
  • These findings reveal a novel mechanism of action for 5-FU in apoptosis and suggest potential for novel combination chemotherapies.
Keywords:
5-FlurouracilCalciumNuclear transportRanTopoisomerase

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