Autophagy is a catabolic process that has been shown to have a role in many cellular processes including the removal of excessive or damaged proteins and protein aggregates. The salivary glands play a critical role in oral health, and their secretory capacity may be critically intertwined with the autophagic process. This review describes the role of autophagy activation in normal salivary gland homeostasis and during the glandular stress responses of therapeutic radiation, ductal ligation, autoimmunity, and salivary gland adenoid cystic carcinoma.
AvilaJLGrundmannOBurdRLimesandKH. 2009. Radiation-induced salivary gland dysfunction results from p53-dependent apoptosis. Int J Radiat Oncol Biol Phys. 73(2):523–529.
2.
BaeHGuanJL. 2011. Suppression of autophagy by FIP200 deletion impairs DNA damage repair and increases cell death upon treatments with anticancer agents. Mol Cancer Res. 9(9):1232–1241.
3.
BozorgiSSProctorGBCarpenterGH. 2014. Rapamycin delays salivary gland atrophy following ductal ligation. Cell Death Dis. 5:e1146.
4.
CadyJ. 2007. Nutritional support during radiotherapy for head and neck cancer: the role of prophylactic feeding tube placement. Clin J Oncol Nurs. 11(6):875–880.
5.
ChenGHuXZhangWXuNWangFQJiaJZhangWFSunZJZhaoYF. 2012. Mammalian target of rapamycin regulates isoliquiritigenin-induced autophagic and apoptotic cell death in adenoid cystic carcinoma cells. Apoptosis. 17(1):90–101.
6.
ChoiAMRyterSWLevineB. 2013. Autophagy in human health and disease. N Engl J Med. 368(7):651–662.
7.
DereticVJiangSDupontN. 2012. Autophagy intersections with conventional and unconventional secretion in tissue development, remodeling and inflammation. Trends Cell Biol. 22(8):397–406.
8.
DewaeleMMaesHAgostinisP. 2010. ROS-mediated mechanisms of autophagy stimulation and their relevance in cancer therapy. Autophagy. 6(7):838–854.
9.
DirixPNuytsSVan denBW. 2006. Radiation-induced xerostomia in patients with head and neck cancer: a literature review. Cancer. 107(11):2525–2534.
10.
FengZZhangHLevineAJJinS. 2005. The coordinate regulation of the p53 and mTOR pathways in cells. Proc Natl Acad Sci U S A. 102(23):8204–8209.
11.
FlodbyPBorokZBanfalviAZhouBGaoDMinooPAnnDKMorriseyEECrandallED. 2010. Directed expression of Cre in alveolar epithelial type 1 cells. Am J Respir Cell Mol Biol. 43(2):173–178.
12.
GeXYYangLQJiangYYangWWFuJLiSL. 2014. Reactive oxygen species and autophagy associated apoptosis and limitation of clonogenic survival induced by zoledronic acid in salivary adenoid cystic carcinoma cell line SACC-83. PLoS ONE. 9(6):e101207.
13.
GlickDBarthSMacleodKF. 2010. Autophagy: cellular and molecular mechanisms. J Pathol. 221(1):3–12.
14.
GrosFArnoldJPageNDécossasMKorganowASMartinTMullerS. 2012. Macroautophagy is deregulated in murine and human lupus T lymphocytes. Autophagy. 8(7):1113–1123.
15.
GrundmannOFillingerJLVictoryKRBurdRLimesandKH. 2010. Restoration of radiation therapy-induced salivary gland dysfunction in mice by post therapy IGF-1 administration. BMC Cancer. 10(1):417.
16.
HancockPJEpsteinJBSadlerGR. 2003. Oral and dental management related to radiation therapy for head and neck cancer. J Can Dent Assoc. 69(9):585–590.
17.
HaraTMatsuiM. 2006. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature. 441:885–889.
18.
Iglesias-BartolomeRPatelVCotrimALeelahavanichkulKMolinoloAAMitchellJBGutkindJS. 2012. mTOR inhibition prevents epithelial stem cell senescence and protects from radiation-induced mucositis. Cell Stem Cell. 11(3):401–414.
19.
JankuFMcConkeyDJHongDSKurzrockR. 2011. Autophagy as a target for anticancer therapy. Nat Rev Clin Oncol. 8(9):528–539.
20.
JiangLHuangSZhangDZhangBLiKLiWZhangSZhangWZhengP. 2014. Inhibition of autophagy augments chemotherapy in human salivary adenoid cystic carcinoma. J Oral Pathol Med. 43(4):265–272.
21.
JiangPMizushimaN. 2014. Autophagy and human diseases. Cell Res. 24(1):69–79.
22.
JungHSChungKWWon KimJKimJKomatsuMTanakaKNguyenYHKangTMYoonKHKimJW. 2008. Loss of autophagy diminishes pancreatic beta cell mass and function with resultant hyperglycemia. Cell Metab. 8(4):318–324.
23.
KatsiougiannisSTentaRSkopouliFN. 2015. Endoplasmic reticulum stress causes autophagy and apoptosis leading to cellular redistribution of the autoantigens Ro/SSA and La/SSB in salivary gland epithelial cells. Clin Exp Immunol. [epub ahead of print 2015 Apr 4] doi:10.1111/cei.12638.
24.
KlionskyDJ. 2007. Autophagy: from phenomenology to molecular understanding in less than a decade. Nat Rev Mol Cell Biol. 8(11):931–937.
25.
KlionskyDJAbdallaFCAbeliovichHAbrahamRTAcevedo-ArozenaAAdeliKAgholmeLAgnelloMAgostinisPAguirre-GhisoJA. 2012. Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy. 8(4):445–544.
26.
KomatsuMWaguriSChibaTMurataSIwataJTanidaIUenoTKoikeMUchiyamaYKominamiE. 2006. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature. 441(7095):880–884.
27.
KomatsuMWaguriSUenoTIwataJMurataSTanidaIEzakiJMizushimaNOhsumiYUchiyamaY. 2005. Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J Cell Biol. 169(3):425–434.
28.
KumaAHatanoMMatsuiMYamamotoANakayaHYoshimoriTOhsumiYTokuhisaTMizushimaN. 2004. The role of autophagy during the early neonatal starvation period. Nature. 432(7020):1032–1036.
29.
LaplanteMSabatiniDM. 2013. Regulation of mTORC1 and its impact on gene expression at a glance. J Cell Sci. 126(Pt 8):1713–1719.
30.
LevineBAbramsJ. 2008. p53: the Janus of autophagy?Nat Cell Biol. 10(6):637–639.
31.
LiangLZMaBLiangYJLiuHCZhangTHZhengGSSuYXLiaoGQ. 2014. Obatoclax induces Beclin 1 and ATG5-dependent apoptosis and autophagy in adenoid cystic carcinoma cells. Oral Dis. 21(4):470–477.
32.
LimesandKHAvilaJLVictoryKChangHHShinYJGrundmannOKleinRR. 2010. IGF-1 preserves salivary gland function following fractionated radiation. Int J Radiat Oncol Biol Phys. 78(2):579–586.
33.
LimesandKHSaidSAndersonSM. 2009. Suppression of radiation-induced salivary gland dysfunction by IGF-1. PLoS ONE. 4(3):e4663.
34.
LinHHLinSMChungYVonderfechtSCamdenJMFlodbyPBorokZLimesandKHMizushimaNAnnDK. 2014. Dynamic involvement of ATG5 in cellular stress responses. Cell Death Dis. 5:e1478.
35.
LiuWHuangSChenZWangHWuHZhangD. 2014. Temsirolimus, the mTOR inhibitor, induces autophagy in adenoid cystic carcinoma: in vitro and in vivo. Pathol Res Pract. 210(11):764–769.
36.
MaBLiangLZLiaoGQLiangYJLiuHCZhengGSSuYX. 2013. Inhibition of autophagy enhances cisplatin cytotoxicity in human adenoid cystic carcinoma cells of salivary glands. J Oral Pathol Med. 42(10):774–780.
37.
MartinetWDe MeyerGRAndriesLHermanAGKockxMM. 2006. Detection of autophagy in tissue by standard immunohistochemistry: possibilities and limitations. Autophagy. 2(1):55–57.
38.
MathewRKarantza-WadsworthVWhiteE. 2007. Role of autophagy in cancer. Nat Rev Cancer. 7(12):961–967.
39.
MizushimaNYoshimoriT. 2007. How to interpret LC3 immunoblotting. Autophagy. 3(6):542–545.
40.
MonneauxFMullerS. 2009. Molecular therapies for systemic lupus erythematosus: clinical trials and future prospects. Arthritis Res Ther. 11(3):234.
41.
Morgan-BathkeMHarrisZIArnettDGKleinRRBurdRAnnDKLimesandKH. 2014. The rapalogue, CCI-779, improves salivary gland function following radiation. PLoS ONE. 9(12):e113183.
42.
Morgan-BathkeMHillGAHarrisZILinHHChiblyAMKleinRRBurdRAnnDKLimesandKH. 2014. Autophagy correlates with maintenance of salivary gland function following radiation. Sci Rep. 4:5206.
43.
Morgan-BathkeMLinHHChiblyAMZhangWSunXChenCHFlodbyPBorokZWuRArnettD. 2013. Deletion of ATG5 shows a role of autophagy in salivary homeostatic control. J Dent Res. 92(10):911–917.
44.
Muhvic-UrekMBralicMCuricSPezelj-RibaricSBorcicJTomacJ. 2006. Imbalance between apoptosis and proliferation causes late radiation damage of salivary gland in mouse. Physiol Res. 55(1):89–95.
45.
NakaiAYamaguchiOTakedaTHiguchiYHikosoSTaniikeMOmiyaSMizoteIMatsumuraYAsahiM. 2007. The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress. Nat Med. 13(5):619–624.
46.
OliveiraJCSouzaKKDiasMMFariaMCRopelleERFloresMBUenoMVellosoLASaadSTSaadMJ. 2008. Antineoplastic effect of rapamycin is potentiated by inhibition of IRS-1 signaling in prostate cancer cells xenografts. J Cancer Res Clin Oncol. 134(8):833–839.
47.
PerlA. 2009. Emerging new pathways of pathogenesis and targets for treatment in systemic lupus erythematosus and Sjogren’s syndrome. Curr Opin Rheumatol. 21(5):443–447.
48.
PeterBVan WaardeMAVissinkAs-GravenmadeEJKoningsAW. 1994. Radiation-induced cell proliferation in the parotid and submandibular glands of the rat. Radiat Res. 140(2):257–265.
49.
PuaHHDzhagalovIChuckMMizushimaNHeYW. 2007. A critical role for the autophagy gene Atg5 in T cell survival and proliferation. J Exp Med. 204(1):25–31.
50.
QuXZouZSunQLuby-PhelpsKChengPHoganRNGilpinCLevineB. 2007. Autophagy gene-dependent clearance of apoptotic cells during embryonic development. Cell. 128(5):931–946.
51.
RabenNHillVSheaLTakikitaSBaumRMizushimaNRalstonEPlotzP. 2008. Suppression of autophagy in skeletal muscle uncovers the accumulation of ubiquitinated proteins and their potential role in muscle damage in Pompe disease. Hum Mol Genet. 17(24):3897–3908.
52.
RadfarLSiroisDA. 2003. Structural and functional injury in minipig salivary glands following fractionated exposure to 70 Gy of ionizing radiation: an animal model for human radiation-induced salivary gland injury. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 96(3):267–274.
53.
RyterSWCloonanSMChoiAM. 2013. Autophagy: a critical regulator of cellular metabolism and homeostasis. Mol Cells. 36(1):7–16.
54.
SarkarSRavikumarBFlotoRARubinszteinDC. 2009. Rapamycin and mTOR-independent autophagy inducers ameliorate toxicity of polyglutamine-expanded huntingtin and related proteinopathies. Cell Death Differ. 16(1):46–56.
55.
SchiaffinoSMammucariCSandriM. 2008. The role of autophagy in neonatal tissues: just a response to amino acid starvation?Autophagy. 4(5):727–730.
56.
SchneiderJLCuervoAM. 2014. Autophagy and human disease: emerging themes. Curr Opin Genet Dev. 26:16–23.
57.
ShintaniTKlionskyDJ. 2004. Autophagy in health and disease: a double-edged sword. Science. 306(5698):990–995.
58.
SilverNProctorGBArnoMCarpenterGH. 2010. Activation of mTOR coincides with autophagy during ligation-induced atrophy in the rat submandibular gland. Cell Death Dis. 1:e14.
59.
SukumaranPSunYVyasMSinghBB. 2015. TRPC1-mediated Ca(2)(+) entry is essential for the regulation of hypoxia and nutrient depletion-dependent autophagy. Cell Death Dis. 6:e1674.
60.
TasdemirEGalluzziLMaiuriMCCriolloAVitaleIHangenEModjtahediNKroemerG. 2008. Methods for assessing autophagy and autophagic cell death. Methods Mol Biol. 445:29–76.
61.
VernonPTangD. 2013. Eat-me: autophagy, phagocytosis, and reactive oxygen species signaling. Antioxid Redox Signal. 18(6):677–691.
62.
WangYFZhangWHeKFLiuBZhangLZhangWFKulkarniABZhaoYFSunZJ. 2014. Induction of autophagy-dependent cell death by the survivin suppressant YM155 in salivary adenoid cystic carcinoma. Apoptosis. 19(4):748–758.
63.
WhiteE. 2012. Deconvoluting the context-dependent role for autophagy in cancer. Nat Rev Cancer. 12(6):401–410.
64.
WirawanEVanden BergheTLippensSAgostinisPVandenabeeleP. 2012. Autophagy: for better or for worse. Cell Res. 22(1):43–61.
65.
XuJYanXGaoRMaoLCotrimAPZhengCZhangCBaumBJWangS. 2010. Effect of irradiation on microvascular endothelial cells of parotid glands in the miniature pig. Int J Radiat Oncol Biol Phys. 78(3):897–903.
ZhangYGoldmanSBaergaRZhaoYKomatsuMJinS. 2009. Adipose-specific deletion of autophagy-related gene 7 (atg7) in mice reveals a role in adipogenesis. Proc Natl Acad Sci U S A. 106(47):19860–19865.
