Targeting Protective Autophagy Exacerbates UV-Triggered Apoptotic Cell Death

被引:35
作者
Chen, Li-Hsin [1 ]
Chu, Pei-Ming [2 ]
Lee, Yi-Jang [3 ]
Tu, Pang-Hsien [4 ]
Chi, Chin-Wen [1 ,5 ]
Lee, Hsin-Chen [1 ]
Chiou, Shih-Hwa [1 ,5 ]
机构
[1] Natl Yang Ming Univ, Sch Med, Inst Pharmacol, Taipei 11221, Taiwan
[2] Natl Def Med Ctr, Grad Inst Life Sci, Taipei 11490, Taiwan
[3] Natl Yang Ming Univ, Sch Biomed Sci & Engn, Dept Biomed Image & Radiol Sci, Taipei 11221, Taiwan
[4] Acad Sinica, Inst Biomed Sci, Taipei 11529, Taiwan
[5] Taipei Vet Gen Hosp, Dept Med Res & Educ, Taipei 11217, Taiwan
关键词
autophagy; apoptosis; UV; DNA-DAMAGE; IONIZING-RADIATION; CANCER-CELLS; ATM; PROTEIN; INHIBITION; MACROAUTOPHAGY; RECRUITMENT; MECHANISMS; INDUCTION;
D O I
10.3390/ijms13011209
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:1209 / 1224
页数:16
相关论文
共 33 条
[1]   Autophagy delays apoptotic death in breast cancer cells following DNA damage [J].
Abedin, M. J. ;
Wang, D. ;
McDonnell, M. A. ;
Lehmann, U. ;
Kelekar, A. .
CELL DEATH AND DIFFERENTIATION, 2007, 14 (03) :500-510
[2]   Recruitment of ATR to sites of ionising radiation-induced DNA damage requires ATM and components of the MRN protein complex [J].
Adams, KE ;
Medhurst, AL ;
Dart, DA ;
Lakin, ND .
ONCOGENE, 2006, 25 (28) :3894-3904
[3]   ATR controls the p21WAF1/Cip1 protein up-regulation and apoptosis in response to low UV fluences [J].
Al-Khalaf, Huda H. ;
Hendrayani, Siti-Faujiah ;
Aboussekhra, Abdelilah .
MOLECULAR CARCINOGENESIS, 2012, 51 (12) :930-938
[4]   ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS [J].
Alexander, Angela ;
Cai, Sheng-Li ;
Kim, Jinhee ;
Nanez, Adrian ;
Sahin, Mustafa ;
MacLean, Kirsteen H. ;
Inoki, Ken ;
Guan, Kun-Liang ;
Shen, Jianjun ;
Person, Maria D. ;
Kusewitt, Donna ;
Mills, Gordon B. ;
Kastan, Michael B. ;
Walker, Cheryl Lyn .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2010, 107 (09) :4153-4158
[5]  
Brown EJ, 2000, GENE DEV, V14, P397
[6]   Differential mechanisms of conjunctival cell death induction by ultraviolet irradiation and benzalkonium chloride [J].
Buron, Nelly ;
Micheau, Olivier ;
Cathelin, Severine ;
Lafontaine, Pierre-Olivier ;
Creuzot-Garcher, Catherine ;
Solary, Eric .
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 2006, 47 (10) :4221-4230
[7]   Autophagy inhibition enhances apoptosis triggered by BO-1051, an N-mustard derivative, and involves the ATM signaling pathway [J].
Chen, Li-Hsin ;
Loong, Che-Chuan ;
Su, Tsann-Long ;
Lee, Yi-Jang ;
Chu, Pei-Ming ;
Tsai, Ming-Long ;
Tsai, Ping-Hsin ;
Tu, Pang-Hsien ;
Chi, Chin-Wen ;
Lee, Hsin-Chen ;
Chiou, Shih-Hwa .
BIOCHEMICAL PHARMACOLOGY, 2011, 81 (05) :594-605
[8]   ATR: an essential regulator of genome integrity [J].
Cimprich, Karlene A. ;
Cortez, David .
NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2008, 9 (08) :616-627
[9]   Autophagy and signaling: their role in cell survival and cell death [J].
Codogno, P ;
Meijer, AJ .
CELL DEATH AND DIFFERENTIATION, 2005, 12 (Suppl 2) :1509-1518
[10]   ATR and ATRIP: Partners in checkpoint signaling [J].
Cortez, D ;
Guntuku, S ;
Qin, J ;
Elledge, SJ .
SCIENCE, 2001, 294 (5547) :1713-1716