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Cancer Discovery
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Inhibition of Nuclear Pore Complex Formation Selectively Induces Cancer Cell Death

Stephen Sakuma, Marcela Raices, Joana Borlido, Valeria Guglielmi, Ethan Y.S. Zhu and Maximiliano A. D'Angelo
Stephen Sakuma
Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California. NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
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Marcela Raices
Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California. NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
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Joana Borlido
Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California. NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
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Valeria Guglielmi
Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California. NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
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Ethan Y.S. Zhu
Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California. NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
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Maximiliano A. D'Angelo
Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California. NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
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  • For correspondence: mdangelo@sbpdiscovery.org
DOI: 10.1158/2159-8290.CD-20-0581 Published January 2021
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Abstract

Nuclear pore complexes (NPC) are the central mediators of nucleocytoplasmic transport. Increasing evidence shows that many cancer cells have increased numbers of NPCs and become addicted to the nuclear transport machinery. How reducing NPC numbers affects the physiology of normal and cancer cells and whether it could be exploited for cancer therapies has not been investigated. We report that inhibition of NPC formation, a process mostly restricted to proliferating cells, causes selective cancer cell death, prevents tumor growth, and induces tumor regression. Although cancer cells die in response to NPC assembly inhibition, normal cells undergo a reversible cell-cycle arrest that allows them to survive. Mechanistically, reducing NPC numbers results in multiple alterations contributing to cancer cell death, including abnormalities in nuclear transport, catastrophic alterations in gene expression, and the selective accumulation of DNA damage. Our findings uncover the NPC formation process as a novel targetable pathway in cancer cells.

Significance: Reducing NPC numbers in cancer cells induces death, prevents tumor growth, and results in tumor regression. Conversely, normal cells undergo a reversible cell-cycle arrest in response to inhibition of NPC assembly. These findings expose the potential of targeting NPC formation in cancer.

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Footnotes

  • Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/).

  • Cancer Discov 2021;11:176–93

  • Received May 1, 2020.
  • Revision received August 3, 2020.
  • Accepted September 15, 2020.
  • Published first September 28, 2020.
  • ©2020 American Association for Cancer Research.
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Cancer Discovery: 11 (1)
January 2021
Volume 11, Issue 1
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Inhibition of Nuclear Pore Complex Formation Selectively Induces Cancer Cell Death
Stephen Sakuma, Marcela Raices, Joana Borlido, Valeria Guglielmi, Ethan Y.S. Zhu and Maximiliano A. D'Angelo
Cancer Discov January 1 2021 (11) (1) 176-193; DOI: 10.1158/2159-8290.CD-20-0581

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Inhibition of Nuclear Pore Complex Formation Selectively Induces Cancer Cell Death
Stephen Sakuma, Marcela Raices, Joana Borlido, Valeria Guglielmi, Ethan Y.S. Zhu and Maximiliano A. D'Angelo
Cancer Discov January 1 2021 (11) (1) 176-193; DOI: 10.1158/2159-8290.CD-20-0581
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