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

Abstract

SummaryDeviating 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.

Diversity and versatility of p38 kinase signalling in health and disease

“…This may be mediated by the p38α phosphorylation and inhibition of Drosha, a key enzyme in miRNA biogenesis whose downregulation sensitizes cells to stress 112 , or by phosphorylation and cytoplasmic translocation of the transcription factor TEAD, which impairs YAP activity, potentially reducing the expression of anti-apoptotic genes 113 . Moreover, p38α activation can induce other stress-induced deleterious effects, although substrates are not characterized, including mitochondrial malfunction 114 , decreased proteasome activity 115 and postmitotic apoptosis mediated by HIF1α inhibition and metabolic stress 116 .…”

“…Of course, target availability is not the only cell-specific factor that determines p38α function. For instance, p38α induces apoptosis when aneuploidy is induced in near-diploid HCT116 cancer cells that have robust mechanisms of genomic stability control 116 , whereas aneuploid cancer cells rely on p38α to engage DNA repair and facilitate survival 117 . It is therefore tempting to speculate that mechanisms linking aneuploidy with p38α-induced apoptosis might be non-operative in some cancer cells, and that the final fate of aneuploid cells may depend on the status of other DNA damage response proteins.…”

On the role of p53 in the cellular response to aneuploidy

“…However, these studies were limited to established human cell lines that were chromosomally stable and near diploid, such as RPE1, an hTERT-immortalized retinal pigmented epithelial cell line; HCT116, a colon carcinoma cell line; and a few other cell lines ( Cianchi et al, 1999 ; Giam et al, 2019 ; Hinchcliffe et al, 2016 ; Janssen et al, 2011 ; Kurinna et al, 2013 ; Li et al, 2010 ; Potapova et al, 2016 ; Santaguida et al, 2017 ; Soto et al, 2017 ; Thompson and Compton, 2010 ). Recent studies also revealed complex interplay between p53 and several other genome-protective proteins, such as p38, H3.3, and BCL9L ( Hinchcliffe et al, 2016 ; López-García et al, 2017 ; Simões-Sousa et al, 2018 ). However, it has been unclear whether a universal signal elicited by abnormal karyotypes may be sensed by the p53 pathway or whether karyotype-specific stress states are sensed through diverse mechanisms and converge upon p53 activation.…”

Hypoxia Induces Drug Resistance in Colorectal Cancer through the HIF-1α/miR-338-5p/IL-6 Feedback Loop

“…Increasing evidence from experimental and clinical studies has revealed that the adaptability of cancer cells to hypoxia is closely related to cancer progression and contributes to the development of resistance to radiation and chemotherapy. [1][2][3][4][5][6] Hypoxia is a common feature of the tumor microenvironment that activates the HIF-signaling pathway in cancer cells. In the case of hypoxia, HIF is reported to be overexpressed in various cancer cells and associated with the progression and adverse clinical outcome of many different tumor entities, including colorectal cancer (CRC).…”