| Autor: |
Simões-Sousa, Susana, Littler, Samantha, Thompson, Sarah L, Minshall, Paul, Whalley, Helen, Bakker, Bjorn, Belkot, Klaudyna, Moralli, Daniela, Bronder, Daniel, Tighe, Anthony, Spierings, Diana C J, Bah, Nourdine, Graham, Joshua, Nelson, Louisa, Green, Catherine M, Foijer, Floris, Townsend, Paul A, Taylor, Stephen S |
| Přispěvatelé: |
Damage and Repair in Cancer Development and Cancer Treatment (DARE), Stem Cell Aging Leukemia and Lymphoma (SALL), Restoring Organ Function by Means of Regenerative Medicine (REGENERATE) |
| Jazyk: |
angličtina |
| Rok vydání: |
2018 |
| Předmět: |
|
| Zdroj: |
Cell reports, 25(3), 749-760. CELL PRESS |
| ISSN: |
2211-1247 |
| Popis: |
Deviating from the normal karyotype dramatically changes gene dosage, in turn decreasing the robustness of biological networks. Consequently, aneuploidy is poorly tolerated by normal somatic cells and acts as a barrier to transformation. Paradoxically, however, karyotype heterogeneity drives tumor evolution and the emergence of therapeutic drug resistance. To better understand how cancer cells tolerate aneuploidy, we focused on the p38 stress response kinase. We show here that p38-deficient cells upregulate glycolysis and avoid post-mitotic apoptosis, leading to the emergence of aneuploid subclones. We also show that p38 deficiency upregulates the hypoxia-inducible transcription factor Hif-1 alpha and that inhibiting Hif-1 alpha restores apoptosis in p38-deficent cells. Because hypoxia and aneuploidy are both barriers to tumor progression, the ability of Hif-1 alpha to promote cell survival following chromosome missegregation raises the possibility that aneuploidy tolerance coevolves with adaptation to hypoxia. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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