The p38α Stress Kinase Suppresses Aneuploidy Tolerance by Inhibiting Hif-1α

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-1α and that inhibiting Hif-1α restores apoptosis in p38-deficent cells. Because hypoxia and aneuploidy are both barriers to tumor progression, the ability of Hif-1α to promote cell survival following chromosome missegregation raises the possibility that aneuploidy tolerance coevolves with adaptation to hypoxia. [Display omitted] •The p38 stress response kinase promotes apoptosis following aneuploidy induction•Aneuploidy-induced metabolic collapse is ameliorated upon inhibition of p38•p38 deficiency upregulates Hif-1α, buffering aneuploidy-induced metabolic collapse•Aneuploidy tolerance may have coevolved with adaptation to hypoxia Simões-Sousa et al. show that chromosome missegregation induces metabolic collapse and apoptosis, mediated by the p38 stress response kinase. Inhibiting p38 elevates Hif-1α, boosts glycolysis, and limits metabolic collapse, in turn allowing expansion of aneuploid clones. Adapting to hypoxia during tumor development may therefore also permit aneuploidy tolerance.