Inhibition of Nuclear Pore Complex Formation Selectively Induces Cancer Cell Death
| Autor: | Maximiliano A. D'Angelo, Valeria Guglielmi, Joana Borlido, Marcela Raices, Stephen Sakuma, Ethan Y.S. Zhu |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
DNA damage Active Transport Cell Nucleus Article 03 medical and health sciences 0302 clinical medicine Neoplasms Gene expression otorhinolaryngologic diseases medicine Humans Tumor growth Nuclear pore Cell Death Chemistry Cancer medicine.disease Nuclear Pore Complex Proteins stomatognathic diseases 030104 developmental biology Oncology Nucleocytoplasmic Transport 030220 oncology & carcinogenesis Cancer cell Nuclear Pore Cancer research Nuclear transport |
| Zdroj: | Cancer Discov |
| ISSN: | 2159-8290 2159-8274 |
| DOI: | 10.1158/2159-8290.cd-20-0581 |
| Popis: | 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. This article is highlighted in the In This Issue feature, p. 1 |
| Databáze: | OpenAIRE |
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