Autophagy Controls p38 Activation to Promote Cell Survival under Genotoxic Stress

Deregulated cell survival under carcinogen-induced genotoxic stress is vital for cancer development. One of the cellular processes critical for cell survival under metabolic stress and energy starvation is autophagy, a catabolic process involved in capture and delivery of cytoplasmic components to lysosomes for degradation. However, the role of autophagy following carcinogen-induced genotoxic stress remains unclear. Here we show that UVB radiation, a known human skin carcinogen that operates by causing DNA damage, induced autophagy and autophagic flux through AMP kinase activation. Autophagy deficiency sensitizes cells to UVB-induced apoptosis through increasing p62-dependent activation of the stress-activated protein kinase p38. Compared with normal human skin, autophagy was activated in human squamous cell carcinomas, in association with decreased phosphorylation of p38, and increased phosphorylation of ATR and formation of γ-H2AX, two markers of DNA damage response. Our results demonstrate that autophagy promotes cell survival through suppressing p62-mediated p38 activation and thus may facilitate tumor development under genotoxic stress. These findings suggest that autophagy plays an oncogenic role in epithelial carcinogenesis by promoting cell survival. Background: The role of autophagy in genotoxic stress remains poorly understood. Results: Autophagy deficiency sensitizes cells to UVB-induced apoptosis through p62-dependent p38 activation. Conclusion: Inhibition of autophagy promotes apoptosis following UVB damage by increasing p38 activation. Significance: These findings identify the vital role of autophagy in cell survival under genotoxic stress and suggest the function of autophagy in cancer pathogenesis.