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Journal of Molecular Medicine

, Volume 93, Issue 1, pp 31–38 | Cite as

Targeting autophagy in skin diseases

  • Teng Yu
  • Joshua Zuber
  • Jinchao LiEmail author
Review

Abstract

Autophagy is a major intracellular degradative process by which cytoplasmic materials are sequestered in double-membraned vesicles and degraded upon fusion with lysosomes. Under normal circumstances, basal autophagy is necessary to maintain cellular homeostasis by scavenging dysfunctional or damaged organelles or proteins. In addition to its vital homeostatic role, this degradation pathway has been implicated in many different cellular processes such as cell apoptosis, inflammation, pathogen clearance, and antigen presentation and thereby has been linked to a variety of human disorders, including metabolic conditions, neurodegenerative diseases, cancers, and infectious diseases. The skin, the largest organ of the body, serves as the first line of defense against many different environmental insults; however, only a few studies have examined the effect of autophagy on the pathogenesis of skin diseases. This review provides an overview of the mechanisms of autophagy and highlights recent findings relevant to the role of autophagy in skin diseases and strategies for therapeutic modulation.

Keywords

Autophagy Psoriasis Systemic lupus erythematosus Vitiligo Infectious skin diseases Cancer 

Notes

Acknowledgments

We apologize to all the authors whose work was not cited or discussed because of space limitations.

Conflict of interest

The authors declare that there is no conflict of interest.

References

  1. 1.
    De Duve C (1963) The lysosome. Sci Am 208:64–72CrossRefGoogle Scholar
  2. 2.
    Mizushima N, Levine B, Cuervo AM, Klionsky DJ (2008) Autophagy fights disease through cellular self-digestion. Nature 451(7182):1069–1075PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Ravikumar B, Sarkar S, Davies JE, Futter M, Garcia-Arencibia M, Green-Thompson ZW, Jimenez-Sanchez M, Korolchuk VI, Lichtenberg M, Luo S et al (2010) Regulation of mammalian autophagy in physiology and pathophysiology. Physiol Rev 90(4):1383–1435PubMedCrossRefGoogle Scholar
  4. 4.
    Deretic V, Saitoh T, Akira S (2013) Autophagy in infection, inflammation and immunity. Nat Rev Immunol 13(10):722–737PubMedCrossRefGoogle Scholar
  5. 5.
    Thurston TL, Wandel MP, von Muhlinen N, Foeglein A, Randow F (2012) Galectin 8 targets damaged vesicles for autophagy to defend cells against bacterial invasion. Nature 482(7385):414–418PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Watson RO, Manzanillo PS, Cox JS (2012) Extracellular M. tuberculosis DNA targets bacteria for autophagy by activating the host DNA-sensing pathway. Cell 150(4):803–815PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Murrow L, Debnath J (2013) Autophagy as a stress-response and quality-control mechanism: implications for cell injury and human disease. Annu Rev Pathol-Mech 8:105–137CrossRefGoogle Scholar
  8. 8.
    Marino G, Niso-Santano M, Baehrecke EH, Kroemer G (2014) Self-consumption: the interplay of autophagy and apoptosis. Nat Rev Mol Cell Biol 15(2):81–94PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Bullon P, Cordero MD, Quiles JL, Ramirez-Tortosa Mdel C, Gonzalez-Alonso A, Alfonsi S, Garcia-Marin R, de Miguel M, Battino M (2012) Autophagy in periodontitis patients and gingival fibroblasts: unraveling the link between chronic diseases and inflammation. BMC Med 10:122PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Sukseree S, Eckhart L, Tschachler E, Watanapokasin R (2013) Autophagy in epithelial homeostasis and defense. Front Biosci (Elite Ed) 5:1000–1010Google Scholar
  11. 11.
    Zhao Y, Zhang CF, Rossiter H, Eckhart L, Konig U, Karner S, Mildner M, Bochkov VN, Tschachler E, Gruber F (2013) Autophagy is induced by UVA and promotes removal of oxidized phospholipids and protein aggregates in epidermal keratinocytes. J Invest Dermatol 133(6):1629–1637PubMedCrossRefGoogle Scholar
  12. 12.
    Griffin LM, Cicchini L, Pyeon D (2013) Human papillomavirus infection is inhibited by host autophagy in primary human keratinocytes. Virology 437(1):12–19PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Lee HM, Shin DM, Yuk JM, Shi G, Choi DK, Lee SH, Huang SM, Kim JM, Kim CD, Lee JH et al (2011) Autophagy negatively regulates keratinocyte inflammatory responses via scaffolding protein p62/SQSTM1. J Immunol 186(2):1248–1258PubMedCrossRefGoogle Scholar
  14. 14.
    Levine B, Kroemer G (2008) Autophagy in the pathogenesis of disease. Cell 132(1):27–42PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Nixon RA (2013) The role of autophagy in neurodegenerative disease. Nat Med 19(8):983–997PubMedCrossRefGoogle Scholar
  16. 16.
    Doria A, Gatto M, Punzi L (2013) Autophagy in human health and disease. N Engl J Med 368(19):1845PubMedCrossRefGoogle Scholar
  17. 17.
    Douroudis K, Kingo K, Traks T, Reimann E, Raud K, Ratsep R, Mossner R, Silm H, Vasar E, Koks S (2012) Polymorphisms in the ATG16L1 gene are associated with psoriasis vulgaris. Acta Derm Venereol 92(1):85–87PubMedCrossRefGoogle Scholar
  18. 18.
    Jeong TJ, Shin MK, Uhm YK, Kim HJ, Chung JH, Lee MH (2010) Association of UVRAG polymorphisms with susceptibility to non-segmental vitiligo in a Korean sample. Exp Dermatol 19(8):e323–e325PubMedCrossRefGoogle Scholar
  19. 19.
    Alessandri C, Barbati C, Vacirca D, Piscopo P, Confaloni A, Sanchez M, Maselli A, Colasanti T, Conti F, Truglia S et al (2012) T lymphocytes from patients with systemic lupus erythematosus are resistant to induction of autophagy. FASEB J 26(11):4722–4732PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Sheen JH, Zoncu R, Kim D, Sabatini DM (2011) Defective regulation of autophagy upon leucine deprivation reveals a targetable liability of human melanoma cells in vitro and in vivo. Cancer Cell 19(5):613–628PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Lee SH, Jeong SK, Ahn SK (2006) An update of the defensive barrier function of skin. Yonsei Med J 47(3):293–306PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Klionsky DJ (2005) The molecular machinery of autophagy: unanswered questions. J Cell Sci 118(Pt 1):7–18PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Suzuki K, Akioka M, Kondo-Kakuta C, Yamamoto H, Ohsumi Y (2013) Fine mapping of autophagy-related proteins during autophagosome formation in Saccharomyces cerevisiae. J Cell Sci 126(Pt 11):2534–2544PubMedCrossRefGoogle Scholar
  24. 24.
    Mulakkal NC, Nagy P, Takats S, Tusco R, Juhasz G, Nezis IP (2014) Autophagy in Drosophila: from historical studies to current knowledge. Biomed Res Int 2014:273473PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Jin M, Klionsky DJ (2014) Regulation of autophagy: modulation of the size and number of autophagosomes. FEBS Lett 588(15):2457–2463PubMedCrossRefGoogle Scholar
  26. 26.
    Alers S, Loffler AS, Wesselborg S, Stork B (2012) Role of AMPK-mTOR-Ulk1/2 in the regulation of autophagy: cross talk, shortcuts, and feedbacks. Mol Cell Biol 32(1):2–11PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Li Y, Chen C, Yao F, Su Q, Liu D, Xue R, Dai G, Fang R, Zeng J, Chen Y et al (2014) AMPK inhibits cardiac hypertrophy by promoting autophagy via mTORC1. Arch Biochem Biophys. doi: 10.1016/j.abb.2014.06.023 Google Scholar
  28. 28.
    Dupont N, Codogno P (2013) Autophagy plays a WASHing game. EMBO J 32(20):2659–2660PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Liang C, Lee JS, Inn KS, Gack MU, Li Q, Roberts EA, Vergne I, Deretic V, Feng P, Akazawa C et al (2008) Beclin1-binding UVRAG targets the class C Vps complex to coordinate autophagosome maturation and endocytic trafficking. Nat Cell Biol 10(7):776–787PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Marquez RT, Xu L (2012) Bcl-2:Beclin 1 complex: multiple, mechanisms regulating autophagy/apoptosis toggle switch. Am J Cancer Res 2(2):214–221PubMedCentralPubMedGoogle Scholar
  31. 31.
    Hanada T, Noda NN, Satomi Y, Ichimura Y, Fujioka Y, Takao T, Inagaki F, Ohsumi Y (2007) The Atg12-Atg5 conjugate has a novel E3-like activity for protein lipidation in autophagy. J Biol Chem 282(52):37298–37302PubMedCrossRefGoogle Scholar
  32. 32.
    Mizushima N, Yoshimori T, Levine B (2010) Methods in mammalian autophagy research. Cell 140(3):313–326PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Rabinowitz JD, White E (2010) Autophagy and metabolism. Science 330(6009):1344–1348PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Jia G, Sowers JR (2014) Autophagy: a housekeeper in cardiorenal metabolic health and disease. Biochim Biophys Acta. doi: 10.1016/j.bbadis.2014.06.025 Google Scholar
  35. 35.
    Hou J, Han ZP, Jing YY, Yang X, Zhang SS, Sun K, Hao C, Meng Y, Yu FH, Liu XQ et al (2013) Autophagy prevents irradiation injury and maintains stemness through decreasing ROS generation in mesenchymal stem cells. Cell Death Dis 4:e844PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Delgado M, Singh S, De Haro S, Master S, Ponpuak M, Dinkins C, Ornatowski W, Vergne I, Deretic V (2009) Autophagy and pattern recognition receptors in innate immunity. Immunol Rev 227:189–202PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Gomes LC, Dikic I (2014) Autophagy in antimicrobial immunity. Mol Cell 54(2):224–233PubMedCrossRefGoogle Scholar
  38. 38.
    Liang XH, Kleeman LK, Jiang HH, Gordon G, Goldman JE, Berry G, Herman B, Levine B (1998) Protection against fatal Sindbis virus encephalitis by beclin, a novel Bcl-2-interacting protein. J Virol 72(11):8586–8596PubMedCentralPubMedGoogle Scholar
  39. 39.
    Gutierrez MG, Master SS, Singh SB, Taylor GA, Colombo MI, Deretic V (2004) Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell 119(6):753–766PubMedCrossRefGoogle Scholar
  40. 40.
    Nakagawa I, Amano A, Mizushima N, Yamamoto A, Yamaguchi H, Kamimoto T, Nara A, Funao J, Nakata M, Tsuda K et al (2004) Autophagy defends cells against invading group A Streptococcus. Science 306(5698):1037–1040PubMedCrossRefGoogle Scholar
  41. 41.
    Mostowy S, Sancho-Shimizu V, Hamon MA, Simeone R, Brosch R, Johansen T, Cossart P (2011) p62 and NDP52 proteins target intracytosolic Shigella and Listeria to different autophagy pathways. J Biol Chem 286(30):26987–26995PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Wild P, Farhan H, McEwan DG, Wagner S, Rogov VV, Brady NR, Richter B, Korac J, Waidmann O, Choudhary C et al (2011) Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth. Science 333(6039):228–233PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Zhao Z, Fux B, Goodwin M, Dunay IR, Strong D, Miller BC, Cadwell K, Delgado MA, Ponpuak M, Green KG et al (2008) Autophagosome-independent essential function for the autophagy protein Atg5 in cellular immunity to intracellular pathogens. Cell Host Microbe 4(5):458–469PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Chong A, Wehrly TD, Child R, Hansen B, Hwang S, Virgin HW, Celli J (2012) Cytosolic clearance of replication-deficient mutants reveals Francisella tularensis interactions with the autophagic pathway. Autophagy 8(9):1342–1356PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Yordy B, Iwasaki A (2013) Cell type-dependent requirement of autophagy in HSV-1 antiviral defense. Autophagy 9(2):236–238PubMedCentralPubMedCrossRefGoogle Scholar
  46. 46.
    Richards AL, Jackson WT (2013) How positive-strand RNA viruses benefit from autophagosome maturation. J Virol 87(18):9966–9972PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Orvedahl A, Levine B (2009) Eating the enemy within: autophagy in infectious diseases. Cell Death Differ 16(1):57–69PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Levine B, Mizushima N, Virgin HW (2011) Autophagy in immunity and inflammation. Nature 469(7330):323–335PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Paludan C, Schmid D, Landthaler M, Vockerodt M, Kube D, Tuschl T, Munz C (2005) Endogenous MHC class II processing of a viral nuclear antigen after autophagy. Science 307(5709):593–596PubMedCrossRefGoogle Scholar
  50. 50.
    English L, Chemali M, Duron J, Rondeau C, Laplante A, Gingras D, Alexander D, Leib D, Norbury C, Lippe R et al (2009) Autophagy enhances the presentation of endogenous viral antigens on MHC class I molecules during HSV-1 infection. Nat Immunol 10(5):480–487PubMedCrossRefGoogle Scholar
  51. 51.
    Pua HH, He YW (2009) Autophagy and lymphocyte homeostasis. Curr Top Microbiol Immunol 335:85–105PubMedGoogle Scholar
  52. 52.
    Lebwohl M (2003) Psoriasis. Lancet 361(9364):1197–1204PubMedCrossRefGoogle Scholar
  53. 53.
    Wang RC, Levinez B (2011) Calcipotriol induces autophagy in HeLa cells and keratinocytes. J Investig Dermatol 131(4):990–993PubMedCentralPubMedCrossRefGoogle Scholar
  54. 54.
    Rajawat Y, Hilioti Z, Bossis I (2010) Autophagy: a target for retinoic acids. Autophagy 6(8):1224–1226PubMedCrossRefGoogle Scholar
  55. 55.
    Anguiano J, Garner TP, Mahalingam M, Das BC, Gavathiotis E, Cuervo AM (2013) Chemical modulation of chaperone-mediated autophagy by retinoic acid derivatives. Nat Chem Biol 9(6):374–382PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    Wu L, Feng Z, Cui S, Hou K, Tang L, Zhou J, Cai G, Xie Y, Hong Q, Fu B et al (2013) Rapamycin upregulates autophagy by inhibiting the mTOR-ULK1 pathway, resulting in reduced podocyte injury. PLoS One 8(5):e63799PubMedCentralPubMedCrossRefGoogle Scholar
  57. 57.
    Yang Y, Wang HP, Wang SY, Xu M, Liu M, Liao MJ, Frank JA, Adhikari S, Bower KA, Shi XL et al (2012) GSK3 beta signaling is involved in ultraviolet B-induced activation of autophagy in epidermal cells. Int J Oncol 41(5):1782–1788PubMedCentralPubMedGoogle Scholar
  58. 58.
    Ramos PS, Brown EE, Kimberly RP, Langefeld CD (2010) Genetic factors predisposing to systemic lupus erythematosus and lupus nephritis. Semin Nephrol 30(2):164–176PubMedCentralPubMedCrossRefGoogle Scholar
  59. 59.
    Gateva V, Sandling JK, Hom G, Taylor KE, Chung SA, Sun X, Ortmann W, Kosoy R, Ferreira RC, Nordmark G et al (2009) A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus. Nat Genet 41(11):1228–1233PubMedCentralPubMedCrossRefGoogle Scholar
  60. 60.
    Han JW, Zheng HF, Cui Y, Sun LD, Ye DQ, Hu Z, Xu JH, Cai ZM, Huang W, Zhao GP et al (2009) Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus. Nat Genet 41(11):1234–1237PubMedCrossRefGoogle Scholar
  61. 61.
    Zhou XJ, Lv JC, Cheng WR, Yu L, Zhao MH, Zhang H (2010) Association of TLR9 gene polymorphisms with lupus nephritis in a Chinese Han population. Clin Exp Rheumatol 28(3):397–400PubMedGoogle Scholar
  62. 62.
    Lee HK, Lund JM, Ramanathan B, Mizushima N, Iwasaki A (2007) Autophagy-dependent viral recognition by plasmacytoid dendritic cells. Science 315(5817):1398–1401PubMedCrossRefGoogle Scholar
  63. 63.
    Gros F, Arnold J, Page N, Decossas M, Korganow AS, Martin T, Muller S (2012) Macroautophagy is deregulated in murine and human lupus T lymphocytes. Autophagy 8(7):1113–1123PubMedCentralPubMedCrossRefGoogle Scholar
  64. 64.
    Clarke AJ, Ellinghaus U, Cortini A, Stranks A, Simon AK, Botto M, Vyse TJ (2014) Autophagy is activated in systemic lupus erythematosus and required for plasmablast development. Ann Rheum Dis. doi: 10.1136/annrheumdis-2013-204343 PubMedCentralGoogle Scholar
  65. 65.
    van Loosdregt J, Spreafico R, Rossetti M, Prakken BJ, Lotz M, Albani S (2013) Hydroxychloroquine preferentially induces apoptosis of CD45RO(+) effector T cells by inhibiting autophagy: a possible mechanism for therapeutic modulation of T cells. J Allergy Clin Immunol 131(5):1443–1446PubMedCentralPubMedCrossRefGoogle Scholar
  66. 66.
    Gros F, Muller S (2014) Pharmacological regulators of autophagy and their link with modulators of lupus disease. Br J Pharmacol. doi: 10.1111/bph.12792 PubMedGoogle Scholar
  67. 67.
    Murase D, Hachiya A, Takano K, Hicks R, Visscher MO, Kitahara T, Hase T, Takema Y, Yoshimori T (2013) Autophagy has a significant role in determining skin color by regulating melanosome degradation in keratinocytes. J Investig Dermatol 133(10):2416–2424PubMedCrossRefGoogle Scholar
  68. 68.
    Kim ES, Jo YK, Park SJ, Chang H, Shin JH, Choi ES, Kim JB, Seok SH, Kim JS, Oh JS et al (2013) ARP101 inhibits alpha-MSH-stimulated melanogenesis by regulation of autophagy in melanocytes. FEBS Lett 587(24):3955–3960PubMedCrossRefGoogle Scholar
  69. 69.
    Kim ES, Chang H, Choi H, Shin JH, Park SJ, Jo YK, Choi ES, Baek SY, Kim BG, Chang JW et al (2014) Autophagy induced by resveratrol suppresses alpha-MSH-induced melanogenesis. Exp Dermatol 23(3):204–206PubMedCrossRefGoogle Scholar
  70. 70.
    Henningham A, Barnett TC, Maamary PG, Walker MJ (2012) Pathogenesis of group A streptococcal infections. Discov Med 13(72):329–342PubMedGoogle Scholar
  71. 71.
    Barnett TC, Liebl D, Seymour LM, Gillen CM, Lim JY, Larock CN, Davies MR, Schulz BL, Nizet V, Teasdale RD et al (2013) The globally disseminated M1T1 clone of group A Streptococcus evades autophagy for intracellular replication. Cell Host Microbe 14(6):675–682PubMedCentralPubMedCrossRefGoogle Scholar
  72. 72.
    Singer AJ, Talan DA (2014) Management of skin abscesses in the era of methicillin-resistant Staphylococcus aureus. N Engl J Med 370(11):1039–1047PubMedCrossRefGoogle Scholar
  73. 73.
    Amano A, Nakagawa I, Yoshimori T (2006) Autophagy in innate immunity against intracellular bacteria. J Biochem 140(2):161–166PubMedCrossRefGoogle Scholar
  74. 74.
    Schnaith A, Kashkar H, Leggio SA, Addicks K, Kronke M, Krut O (2007) Staphylococcus aureus subvert autophagy for induction of caspase-independent host cell death. J Biol Chem 282(4):2695–2706PubMedCrossRefGoogle Scholar
  75. 75.
    Lenz HD, Haller E, Melzer E, Kober K, Wurster K, Stahl M, Bassham DC, Vierstra RD, Parker JE, Bautor J et al (2011) Autophagy differentially controls plant basal immunity to biotrophic and necrotrophic pathogens. Plant J 66(5):818–830PubMedCrossRefGoogle Scholar
  76. 76.
    Qin QM, Luo JJ, Lin XR, Pei JW, Li L, Ficht TA, de Figueiredo P (2011) Functional analysis of host factors that mediate the intracellular lifestyle of Cryptococcus neoformans. PLoS Pathog 7(6):e1002078PubMedCentralPubMedCrossRefGoogle Scholar
  77. 77.
    Nicola AM, Albuquerque P, Martinez LR, Dal-Rosso RA, Saylor C, De Jesus M, Nosanchuk JD, Casadevall A (2012) Macrophage autophagy in immunity to Cryptococcus neoformans and Candida albicans. Infect Immun 80(9):3065–3076PubMedCentralPubMedCrossRefGoogle Scholar
  78. 78.
    Masperi P, Dall'Olio G, Calefano A, Vannini GL (1984) Autophagic vacuole development in Trichophyton mentagrophytes exposed in vitro to miconazole. Sabouraudia 22(1):27–35PubMedCrossRefGoogle Scholar
  79. 79.
    Orvedahl A, Alexander D, Talloczy Z, Sun Q, Wei Y, Zhang W, Burns D, Leib DA, Levine B (2007) HSV-1 ICP34.5 confers neurovirulence by targeting the Beclin 1 autophagy protein. Cell Host Microbe 1(1):23–35PubMedCrossRefGoogle Scholar
  80. 80.
    Lee HK, Mattei LM, Steinberg BE, Alberts P, Lee YH, Chervonsky A, Mizushima N, Grinstein S, Iwasaki A (2010) In vivo requirement for Atg5 in antigen presentation by dendritic cells. Immunity 32(2):227–239PubMedCentralPubMedCrossRefGoogle Scholar
  81. 81.
    Guo JY, Xia B, White E (2013) Autophagy-mediated tumor promotion. Cell 155(6):1216–1219PubMedCentralPubMedCrossRefGoogle Scholar
  82. 82.
    White E (2012) Deconvoluting the context-dependent role for autophagy in cancer. Nat Rev Cancer 12(6):401–410PubMedCentralPubMedCrossRefGoogle Scholar
  83. 83.
    Choi KS (2012) Autophagy and cancer. Exp Mol Med 44(2):109–120PubMedCentralPubMedCrossRefGoogle Scholar
  84. 84.
    Mathew R, Karp CM, Beaudoin B, Vuong N, Chen GH, Chen HY, Bray K, Reddy A, Bhanot G, Gelinas C et al (2009) Autophagy suppresses tumorigenesis through elimination of p62. Cell 137(6):1062–1075PubMedCentralPubMedCrossRefGoogle Scholar
  85. 85.
    Qu X, Yu J, Bhagat G, Furuya N, Hibshoosh H, Troxel A, Rosen J, Eskelinen EL, Mizushima N, Ohsumi Y et al (2003) Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J Clin Invest 112(12):1809–1820PubMedCentralPubMedCrossRefGoogle Scholar
  86. 86.
    Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, Levine B (1999) Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 402(6762):672–676PubMedCrossRefGoogle Scholar
  87. 87.
    Yue ZY, Jin SK, Yang CW, Levine AJ, Heintz N (2003) Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc Natl Acad Sci U S A 100(25):15077–15082PubMedCentralPubMedCrossRefGoogle Scholar
  88. 88.
    Degenhardt K, Mathew R, Beaudoin B, Bray K, Anderson D, Chen G, Mukherjee C, Shi Y, Gelinas C, Fan Y et al (2006) Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell 10(1):51–64PubMedCentralPubMedCrossRefGoogle Scholar
  89. 89.
    White E, DiPaola RS (2009) The double-edged sword of autophagy modulation in cancer. Clin Cancer Res 15(17):5308–5316PubMedCentralPubMedCrossRefGoogle Scholar
  90. 90.
    Sivridis E, Giatromanolaki A, Karpathiou G, Karpouzis A, Kouskoukis C, Koukourakis MI (2011) LC3A-positive "stone-like" structures in cutaneous squamous cell carcinomas. Am J Dermatopathol 33(3):285–290PubMedCrossRefGoogle Scholar
  91. 91.
    Qiang L, Wu C, Ming M, Viollet B, He YY (2013) Autophagy controls p38 activation to promote cell survival under genotoxic stress. J Biol Chem 288(3):1603–1611PubMedCentralPubMedCrossRefGoogle Scholar
  92. 92.
    Lazova R, Camp RL, Klump V, Siddiqui SF, Amaravadi RK, Pawelek JM (2012) Punctate LC3B expression is a common feature of solid tumors and associated with proliferation, metastasis, and poor outcome. Clin Cancer Res 18(2):370–379PubMedCrossRefGoogle Scholar
  93. 93.
    Ma XH, Piao S, Wang D, McAfee QW, Nathanson KL, Lum JJ, Li LZ, Amaravadi RK (2011) Measurements of tumor cell autophagy predict invasiveness, resistance to chemotherapy, and survival in melanoma. Clin Cancer Res 17(10):3478–3489PubMedCentralPubMedCrossRefGoogle Scholar
  94. 94.
    Verschooten L, Barrette K, Van Kelst S, Rubio Romero N, Proby C, De Vos R, Agostinis P, Garmyn M (2012) Autophagy inhibitor chloroquine enhanced the cell death inducing effect of the flavonoid luteolin in metastatic squamous cell carcinoma cells. PLoS One 7(10):e48264PubMedCentralPubMedCrossRefGoogle Scholar
  95. 95.
    Ma XH, Piao SF, Dey S, Mcafee Q, Karakousis G, Villanueva J, Hart LS, Levi S, Hu J, Zhang G et al (2014) Targeting ER stress-induced autophagy overcomes BRAF inhibitor resistance in melanoma. J Clin Investig 124(3):1406–1417PubMedCentralPubMedCrossRefGoogle Scholar
  96. 96.
    Rangwala R, Chang YC, Hu J, Algazy K, Evans T, Fecher L, Schuchter L, Torigian DA, Panosian J, Troxel A et al (2014) Combined MTOR and autophagy inhibition: Phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma. Autophagy 10(8):1391–1402PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Department of DermatologyShandong Jining No.1 People’s HospitalJiningChina
  2. 2.Department of Biochemistry and Molecular Biology, College of Natural SciencesUniversity of MassachusettsAmherstUSA
  3. 3.Department of Nutrition, School of Public Health and Health SciencesUniversity of MassachusettsAmherstUSA

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