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The p38 alpha stress kinase suppresses aneuploidy tolerance by inhibiting Hif-1 alpha.
Simoes-Sousa, Susana Littler, Samantha Thompson, Sarah L Minshall, Paul Whalley, Helen J Bakker, B Belkot, Klaudyna Moralli, D Bronder, Daniel Tighe, Anthony
Simoes-Sousa, Susana
Littler, Samantha
Thompson, Sarah L
Minshall, Paul
Whalley, Helen J
Bakker, B
Belkot, Klaudyna
Moralli, D
Bronder, Daniel
Tighe, Anthony
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Abstract
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? and that inhibiting Hif-1? restores apoptosis in p38-deficent cells. Because hypoxia and aneuploidy are both barriers to tumor progression, the ability of Hif-1? to promote cell survival following chromosome missegregation raises the possibility that aneuploidy tolerance coevolves with adaptation to hypoxia.
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Date
2018
Publisher
Collections
Keywords
Type
Article
Citation
Simoes-Sousa S, Littler S, Thompson SL, Minshall P, Whalley H, Bakker B, et al. The p38 alpha stress kinase suppresses aneuploidy tolerance by inhibiting Hif-1 alpha. Cell Rep. 2018 Oct 16;25(3):749-60 e6.