ΔNp63 inhibits oxidative stress-induced cell death, including ferroptosis, and cooperates with the BCL-2 family to promote clonogenic survival Journal Article
| Authors: | Wang, G. X.; Tu, H. C.; Dong, Y.; Skanderup, A. J.; Wang, Y.; Takeda, S.; Ganesan, Y. T.; Han, S.; Liu, H.; Hsieh, J. J.; Cheng, E. H. |
| Article Title: | ΔNp63 inhibits oxidative stress-induced cell death, including ferroptosis, and cooperates with the BCL-2 family to promote clonogenic survival |
| Abstract: | The BCL-2 family proteins are central regulators of apoptosis. However, cells deficient for BAX and BAK or overexpressing BCL-2 still succumb to oxidative stress upon DNA damage or matrix detachment. Here, we show that ΔNp63α overexpression protects cells from oxidative stress induced by oxidants, DNA damage, anoikis, or ferroptosis-inducing agents. Conversely, ΔNp63α deficiency increases oxidative stress. Mechanistically, ΔNp63α orchestrates redox homeostasis through transcriptional control of glutathione biogenesis, utilization, and regeneration. Analysis of a lung squamous cell carcinoma dataset from The Cancer Genome Atlas (TCGA) reveals that TP63 amplification/overexpression upregulates the glutathione metabolism pathway in primary human tumors. Strikingly, overexpression of ΔNp63α promotes clonogenic survival of p53−/−Bax−/−Bak−/− cells against DNA damage. Furthermore, co-expression of BCL-2 and ΔNp63α confers clonogenic survival against matrix detachment, disrupts the luminal clearance of mammary acini, and promotes cancer metastasis. Our findings highlight the need for a simultaneous blockade of apoptosis and oxidative stress to promote long-term cellular well-being. Apoptosis-defective cells remain vulnerable to oxidative stress, which limits long-term survival. Wang et al. identify ΔNp63α as a central regulator of redox homeostasis through transcriptional control of a tightly coupled glutathione metabolic circuit. ΔNp63α alleviates oxidative stress and cooperates with the BCL-2 family to promote both long-term cellular well-being and cancer metastasis. © 2017 The Author(s) |
| Keywords: | human cell; nonhuman; animal cell; mouse; cell death; dna damage; cell survival; gene overexpression; protein bcl 2; metastasis; apoptosis; gene amplification; embryo; animal experiment; necrosis; protein p53; oncogene; transcription regulation; oxidative stress; cell regeneration; homeostasis; cell protection; oxidation reduction reaction; glutathione; biogenesis; clonogenesis; tp63; tp63 gene; bcl-2; protein bax; ros; protein bak; ferroptosis; redox; anoikis; human; priority journal; article; glutathione metabolism; squamous cell lung carcinoma; programmed necrotic death; deltanp63 gene |
| Journal Title: | Cell Reports |
| Volume: | 21 |
| Issue: | 10 |
| ISSN: | 2211-1247 |
| Publisher: | Cell Press |
| Date Published: | 2017-12-05 |
| Start Page: | 2926 |
| End Page: | 2939 |
| Language: | English |
| DOI: | 10.1016/j.celrep.2017.11.030 |
| PROVIDER: | scopus |
| PUBMED: | 29212036 |
| PMCID: | PMC5915869 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 January 2018 -- Source: Scopus |
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