A regulatory pathway of autophagy and tumor

23 1 2011 1 Chinese Bulletin of Life Sciences Vol. 23, No. 1 Jan., 2011 (1 110001 2 110001) mtor Beclin1 mto R B e c lin 1 Q25; R730. 239 A A regulatory pathway of autophagy and tumor ZHANG Xiu-Chun 1, LI Dan-Ni, LI Feng 2 * (1 College of Clinical Medicine, China Medical University, Shenyang 110001, China; 2 Key Laboratory of Cell Biology of Ministry of Public Health and Key Laboratory of Medical Cell Biology of Ministry of Education, Department of Cell Biology, College of Basic Medical Science, China Medical University, Shenyang 110001, China) Abstract: Autophagy is a process of self-degradation of cellular components, in which double-membrane autophagosome sequester organelles or portions of cytosol and fuse with lysosomes for breakdown. It has the unique morphological changes and specific regulatory pathways. As the convergences of various pathways, mtor complex and Beclin1 complex play a crucial role in the regulation of autophagy. On the one hand, autophagy maintains cell homeostasis by elimating damaged organelles, as well as removing misfolded or aggregated proteins. On the other hand, it also can result in cell death. A growing body of evidence indicates that autophagy is associated with a number of diseases, especially the cancer, and is the double-edged sword in the modulation of cancer. Key words: autophagy mtor Beclin1 tumor phagy ( ) [1] 2010-06-12 2010-06-29 ( 3 0 7 7 1 1 2 8 9 0 8 1 3 0 3 8 ) ( 8 6 3 ) ( ) ( 2 0 0 7 A A 0 2 Z 3 0 5 ) (20087195) PAS(pre-autophagosomal structure) [2] [3] a u t o ( ) E-mail: fil@mail.cmu.edu.cn

2 0 20 50 ( ) 31 Atg [4] [7] (autophagy related gene) Atg (1)Atg1-Atg11-Atg17-Atg20-Atg24-Atg29-Atg31 Atg13-Atg8 mtor mtor mtor Atg13 Atg1 [5] Atg1 m T O R A tg 13 A tg 1 [8,9] Atg1 [6] ( 1 ) (2)Atg6-Atg14-Vps34-Vps15

2 1 Vps34 Class PI3K Atg7 Atg3 LC3-I- PI Atg3 LC3-I C PE PI3P LC3-II-PE [10] Atg21 PAS LC3-II [10,11] [12] Atg24 ( 1) Atg4 Atg12-Atg5 (3) Atg12-Atg5-Atg16 LC3-II-PE ( 2) [12] Atg12 Atg5 Atg7 Atg10 [13] Atg7 ATP II Atg3 Atg12 Atg5 Atg12 Atg12-Atg5 Atg12 Atg10 Atg12- Atg10 Atg12-Atg5 Atg5 Atg16 Atg5 Atg12-Atg5-Atg16 Atg12-Atg5 Atg16 [14] LC3-II-PE Atg10 LC3-I A t g1 2 A tg 5 LC3-II-PE Atg12- PAS LC3- Atg12-Atg5 II-PE Atg4 [12] [10] LC3-II-PE ( 1) LC(Atg8 ) Atg4 (4)

2 2 Akt Akt mtor LAMP1 LAMP2 GTP Rab7 UVRAG(the protein product of the ultraviolet-radiation-resistance-associated gene) UVRAG Beclin1 Vps34 (tethering protein Beclin1 ) Rab7 [15] PTEN class PI3K PTEN Akt [19] class PI3K/AKT class PI3K(Vps34) Beclin1 Bcl-2 Beclin1 UVRAG Vps34 Beclin1/Vps34 Beclin1 mtor Beclin1 ( 2) (1)Bcl-2 UVRAG DAPK(death-associated protein kinase DAPK) CDK Atg (2)Vps34 PI3P [16] 30 Atg Atg mtor Atg mtor Vps34 class PI3K class PI3K mtor class PI3K mtor (PI) PI3P PI(3,4)P2 PI(3,4,5) mtorc1 P3 Vps34 Beclin1 (ECD) (mt OR Gβ L ra pt or ) mt OR C2 (1) ( m T O R m L S T 8 r i c t o r S I N 1 p r o t o r ) PI3P mtorc1 [20] (2) mtorc2 mtor / [21] mtor Beclin 1 [17] mtor Bcl-2 (1)mTOR (BH3) (CCD) 4E-BP1( ( E C D ) 4E 1) S6K1 ( S6 Beclin1 ) [15,18] Bcl-2 UVRAG (2) mtor Atg Beclin1 Bcl-2 mtor [22] mtor Beclin1 BH3 Beclin1 Vps34 PI3K-AKT Atg PI3K-AKT mtor PAS AMPK AMP/ATP c- m T O R Jun N JNK1 Bcl-2 PI3K-AKT PI3K [23] Beclin1 class PI3K Bcl-2 Beclin1 class PI3K PIP2 PIP3 Beclin1

2 3 Bcl-2 JNK 3 h HeLa DAPK Bcl-2 BH3 [24] UVRAG Beclin1 Beclin1 CCD UVRAG Beclin1 Vps34 [20] Cdk1 Cdk5 Vps34 PI3P Cdk1 T159 Vps34 Vps34 Beclin1 Cdk5 Vps34 T159 T668 T668 1/3 [25] Vps34 [ 6 ] mtor Beclin1 mtor Beclin1 Vps34 V p s 3 4 mtor Vps34 Beclin1 Vps34 Vps34 mtor [26,27] [31] Beclin1 Qu [36] beclin1 +/- Ahn [28] Ding Beclin1 103 [37] 44 60 Beclin1 9 5 % 8 3 % Beclin1 Beclin1 Tang [29] HBV Beclin1 DNA mrna Beclin1 [1,38] DNA Beclin1 4% 37% [32] [33-35] ( ) mtor Beclin1 [30] [31]

2 4 [15] Rosenfeldt MT, Ryan KM. The role of autophagy in tumour development and cancer therapy. Exp Rev Mol Med, (1) Miracco 2009, 11: e36 [39] [16] Nakatogawa H, Suzuki K, Kamada Y, et al. Dynamics and (2) diversity in autophagy mechanisms: lessons from yeast. Nat Toth [40] Rev Mol Cell Biol, 2009, 10(7): 458-67 [17] Glick D, Barth S, Macleod KF. Autophagy: cellular and molecular mechanism. J Pathol, 2010, 221(1): 3-12 [18] Scott RC, Schuldiner O, Neufeld TP. Role and regulation of starvation-induced autophagy in the Drosophila fat body. Dev Cell, 2004, 7(2): 167-78 [19] Arico S, Petiot A, Bauvy C, et al. The tumor suppressor Beclinl PTEN positively regulates macroautophagy by inhibiting the phosphatidylinositol 3-kinase/protein kinase B pathway. J Biol Chem, 2001, 276(38): 35243-6 [20] Backer J. The regulation and function of Class PI3Ks: novel roles for Vps34. Biochem J, 2008, 410(1): 1-17 [21] Sun Q, Fan W, Zhong Q. Regulation of Beclin1 in autophagy. Autophagy, 2009, 5(5): 713-6 [22] Levine B, Sinha S, Kroemer G. Bcl-2 family members: dual [1] Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell, 2008, 132(1): 27-42 regulators of apoptosis and autophagy. Autophagy, 2008, 4 (5): 600-6 [2] Hayashi-Nishino M, Fujita N, Noda T, et al. A subdomain of the endoplasmic reticulum forms a cradle for autophagosome formation. Nat Cell Biol, 2009, 11(12): 1433-7 [23] Wei Y, Pattingre S, Sinha S, et al. JNK1-mediated phosphorylation of Bcl-2 regulates starvation-induced autophagy. Mol Cell, 2008, 30(6): 678-88 [3] Hamasaki M, Yoshimori T. Where do they come from? Insights into autophagosome formation. FEBS Lett, 2010, 584 [24] Zalckvar E, Berissi H, Mizrachy L, et al. DAP-kinase-mediated phosphorylation on the BH3 domain of beclin1 promotes [4] dissociation of beclin1 from Bcl-X L (7): 1296-301 and induction of Kuma A, Hatano M, Matsui M, et al. The role of autophagy autophagy. EMBO Rep, 2009, 10(3): 285-92 during the early neonatal starvation period. Nature, 2004, 432(7020): 1032-6 [25] Rubinsztein DC. Cdks regulate autophagy via Vps34. Mol Cell, 2010, 38(4): 483-4 [5] Hara T, Nakamura K, Matsui M, et a1. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature, 2006, 441(7095): 885-9 [26] Dann SG, Thomas G. The amino acid sensitive TOR pathway from yeast to mammals. FEBS Lett, 2006, 580(12): 2821-9 [6] Barth S, Glick D, Macleod KF. Autophagy: assays and artifacts. J Pathol, 2010, 221(2): 117-24 [27] Nobukuni T, Kozma SC, Thomas G. hvps34, an ancient player, enters a growing game: mtor complex1/s6k1 [7] Levine B, Yuan J. Autophagy in cell death: an innocent signaling. Curr Opin Cell Biol, 2007, 19(2): 135-41 convict. J Clin Invest, 2005, 115(10): 2679-88 [28] Ahn CH, Jeong EG, Lee JW, et al. Expression of beclin-1, an [8] Rubinsztein DC. Autophagy: where next. EMBO Rep, 2010, 11(1): 3 autophagy-related protein, in gastric and colorectal cancers. APMIS, 2007, 115(12): 1344-9 [9] Pattingre S, Espert L, Biard-Piechaczyk M, et al. Regulation of macroautophagy by mtor and Beclin 1 complexes. Biochimie, 2008, 90(2): 313-23 [29] Tang H, Da L, Mao Y, et al. Hepatitis B virus X protein sensitizes cells to starvation-induced autophagy via up-regulation of Beclin 1 expression. Hepatology, 2009, 49(1): 61- [10] Yang Z, Klionsky DJ. An overview of the molecular mechanism 71 of autophagy. Curr Top Microbiol Immunol, 2009, 335: 1-32 [30] Karantza-Wadsworth V, White E. Role of autophagy in breast cancer. Autophagy, 2007, 3(6): 610-3 [11] He C, Klionsky DJ. Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet, 2009, 43: 67-93 [31] Sun Y, Liu JH, Jin L, et al. Over-expression of the Beclin1 gene upregulates chemosensitivity to anti-cancer drugs by [12] Geng J, Klionsky DJ. The Atg8 and Atg12 ubiquitin-like conjugation systems in macroautophagy. EMBO Rep, 2008, enhancing therapy-induced apoptosis in cervix squamous carcinoma CaSki cells. Cancer Lett, 2010, 294(2): 204-10 9(9): 859-64 [32] Li GD, Wu DQ, Li BY. Research progresses on the role of [13] Ravikumar B, Futter M, Rubinsztein DC, et al. Mammalian cell autophagy in cancer. Chn J Cancer, 2009, 28(4): 445-8 macroautophagy at a glance. J Cell Sci, 2009, 122(Pt 11): 1707-11 [33] Jin S, Dipaola RS, Mathew R, et al. Metabolic catastrophe as a means to cancer cell death. J Cell Sci, 2007, 120(Pt3): [14] Mizushima N, Yamamoto A, Hatano M, et al. Dissection of 379-83 autophagosome formation using Apg5-deficient mouse embryonic stem cells. J Cell Biol, 2001, 152(4): 657-67 [34] Degenhardt K, Mathew R, Beaudoin B, et al. Autophagy promotes tumor cell survival and restricts necrosis,

2 5 inflammation, and tumorgenesis. Cancer Cell, 2006, 10(1): 51-64 [35] Lum JJ, Bauer DE, Kong M, et al. Growth factor regulation of autophagy and cell survival in the absence of apoptosis. Cell, 2005, 120(2): 237-48 [36] Qu X, Yu J, Bhagat G, et al. Promotion of tumorigenesis by heterozygous disruption of the beclin1 autophagy gene. J Clin Invest, 2003, 112(12): 1809-20 [37] Ding ZB, Shi YH, Zhou J, et al. Association of autophagy defect with a malignant phenotype and poor prognosis of hepatocellular carcinoma. Cancer Res, 2008, 68(22): 9167-75 [38] Jin S, White E. Role of autophagy in cancer: management of metabolic stress. Autophagy, 2007, 3(1): 28-31 [39] Miracco C, Cosci E, Oliveri G, et al. Protein and mrna expression of autophagy gene Beclin 1 in human brain tumours. Int J Oncol, 2007, 30(2): 429-36 [40] Toth S, Nagy K, Palfla Z, et al. Cellular autophagic capacity changes during azaserine-induced tumor progression in the rat pancreas. Up-regulation in all premalignant stages and down-regulation with loss of cycloheximide sensitivity of segregation along with malignant transformation. Cell Tissue Res, 2002, 309(3): 409-16