Targeting protective autophagy exacerbates UV-triggered apoptotic cell death.
Autophagy is activated by various stresses, including DNA damage, and previous studies of DNA damage-induced autophagy have focused on the response to chemotherapeutic drugs, ionizing radiation, and reactive oxygen species. In this study, we investigated the biological significance of autophagic response to ultraviolet (UV) irradiation in A549 and H1299 cells. Our results indicated that UV induces on-rate autophagic flux in these cells. Autophagy inhibition resulting from the knockdown of beclin-1 and Atg5 reduced cell viability and enhanced apoptosis. Moreover, we found that ATR phosphorylation was accompanied by microtubule-associated protein 1 light chain 3B II (LC3B-II) expression during the early phases following UV irradiation, which is a well-established inducer of ATR. Knocking down ATR further attenuated the reduction in LC3B-II at early stages in response to UV treatment. Despite the potential role of ATR in autophagic response, reduced ATR expression does not affect autophagy induction during late phases (24 and 48 h after UV treatment). The result is consistent with the reduced ATR phosphorylation at the same time points and suggests that autophagic response at this stage is activated via a distinct pathway. In conclusion, this study demonstrated that autophagy acts as a cytoprotective mechanism against UV-induced apoptosis and that autophagy induction accompanied with apoptosis at late stages is independent of ATR activation.
Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei 11221, Taiwan.
Li-Hsin
LH
Chen
Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 11490, Taiwan.
Pei-Ming
PM
Chu
Department of Biomedical Image and Radiological Sciences, School of Biomedical Science and Engineering, National Yang-Ming University, Taipei 11221, Taiwan.
Yi-Jang
YJ
Lee
Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.
Pang-Hsien
PH
Tu
Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei 11221, Taiwan.|Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei 11217, Taiwan.
Chin-Wen
CW
Chi
Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei 11221, Taiwan.
Hsin-Chen
HC
Lee
Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei 11221, Taiwan.|Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei 11217, Taiwan.
Shih-Hwa
SH
Chiou
D017209:Apoptosis / Q000528:radiation effects; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D001343:Autophagy / Q000528:radiation effects*; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000528:radiation effects; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000528:radiation effects; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000528:radiation effects; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D013997:Time Factors; D014466:Ultraviolet Rays
C502778:ATG5 protein, human; D051017:Apoptosis Regulatory Proteins; D000071187:Autophagy-Related Protein 5; C491997:BECN1 protein, human; D000071186:Beclin-1; C477012:MAP1LC3A protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins