Expression and regulation of aldehyde dehydrogenases in prostate cancer

Abstract

The functional role of aldehyde dehydrogenases (ALDHs) in prostate cancer remains an area of some controversy. Many studies have used high ALDH functional activity to isolate putative cancer stem cells with tumour-initiating and propagating properties, while evidence is also emerging about the involvement of specific isoforms in migration, invasiveness and metastasis. Identification of specific ALDH isoforms, which contribute to both drug resistance and aggressiveness of the disease remains a challenge within the complex heterogeneity of prostate cancer. The purpose of this perspective is to dissect functional roles for ALDH in the tumour microenvironment and to evaluate the potential of the ALDH gene family as biomarkers and/or targets for therapeutic intervention.

Keywords

Aldehyde dehydrogenase / retinoic acid / prostate cancer / castration-resistant prostate cancer / cancer stem cells / multidrug resistance

References

[1] Ramalingam S,Njar VC.Dissecting major signaling pathways in prostate cancer development and progression: mechanisms and novel therapeutic targets.J Steroid Biochem Mol Biol2017;166:16-27

[2] Loblaw DA,Nam R,Ben-Josef E,Middleton R,Smith TJ,Taplin M,Wade JL3rd,Scher HI.Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2006 update of an American Society of Clinical Oncology practice guideline.J Clin Oncol2007;25:1596-605

[3] Pienta KJ.Mechanisms underlying the development of androgen-independent prostate cancer.Clin Cancer Res2006;12:1665-71

[4] Vermeulen L,van der Heijden M,de Jong JH,Tuynman JB,Merz C,Sprick MR,Richel DJ,Medema JP.Wnt activity defines colon cancer stem cells and is regulated by the microenvironment.Nat Cell Biol2010;12:468-76

[5] Morrissey C.The role of tumor microenvironment in prostate cancer bone metastasis.J Cell Biochem2007;101:873-86

[6] Barron DA.The reactive stroma microenvironment and prostate cancer progression.Endocr Relat Cancer2012;19:R187-204 PMCID:PMC3716392

[7] Karlou M,Efstathiou E.Therapeutic targeting of the prostate cancer microenvironment.Nat Rev Urol2010;7:494-509

[8] Zhu ML.Androgen receptor and growth factor signaling cross-talk in prostate cancer cells.Endocr Relat Cancer2008;15:841-9 PMCID:PMC2740735

[9] Yauch RL,Scales SJ,Tian H,Marshall D,Januario T,Nannini-Pepe M,Marsters JC,de Sauvage FJ.A paracrine requirement for hedgehog signalling in cancer.Nature2008;455:406-10

[10] Grose R.Fibroblast growth factor signaling in tumorigenesis.Cytokine Growth Factor Rev2005;16:179-86

[11] Nam S,Cheng JQ,Lee JH,Mirosevich J,Jove R.Action of the Src family kinase inhibitor, dasatinib (BMS-354825), on human prostate cancer cells.Cancer Res2005;65:9185-9

[12] Bhowmick NA,Plieth D,Dumont N,Washington MK,Moses HL.TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia.Science2004;303:848-51

[13] Goel HL,Kogan S.Integrins in prostate cancer progression.Endocr Relat Cancer2008;15:657-64 PMCID:PMC2668544

[14] Shou JY,Koeppen H,Gao WQ.Dynamics of notch expression during murine prostate development and tumorigenesis.Cancer Res2001;61:7291-7

[15] van den Hoogen C,Cheung H,Lippitt JM,Hamdy FC,Thalmann GN,Pelger RC.High aldehyde dehydrogenase activity identifies tumor-initiating and metastasis-initiating cells in human prostate cancer.Cancer Res2010;70:5163-73

[16] Clarke MF,Dirks PB,Jamieson CH,Visvader J,Wahl GM.Cancer stem cells--perspectives on current status and future directions: AACR Workshop on cancer stem cells.Cancer Res2006;66:9339-44

[17] Zhang JW,Ye L,He X,Ross J,Johnson T,Harris S,Mishina Y.Identification of the haematopoietic stem cell niche and control of the niche size.Nature2003;425:836-41

[18] Suda T,Hirao A.Hematopoietic stem cells and their niche.Trends Immunol2005;26:426-33

[19] Borovski T,Vermeulen L.Cancer stem cell niche: the place to be.Cancer Res2011;71:634-9

[20] Yi SY,Nan KJ.Cancer stem cells niche: a target for novel cancer therapeutics.Cancer Treat Rev2013;39:290-6

[21] Maitland NJ.Prostate cancer stem cells: a new target for therapy.J Clin Oncol2008;26:2862-70

[22] Maitland NJ.Cancer stem cells - a therapeutic target?.Curr Opin Mol Ther2010;12:662-73

[23] Kozma E,Squarcialupi L,Moro S,Spalluto G.Fluorescent ligands for adenosine receptors.Bioorg Med Chem Lett2013;23:26-36 PMCID:PMC3557833

[24] Marchitti SA,Stagos D.Non-P450 aldehyde oxidizing enzymes: the aldehyde dehydrogenase superfamily.Expert Opin Drug Metab Toxicol2008;4:697-720 PMCID:PMC2658643

[25] Vasiliou V.Analysis and update of the human aldehyde dehydrogenase (ALDH) gene family.Hum Genomics2005;2:138-43 PMCID:PMC3525259

[26] Sladek NE.Human aldehyde dehydrogenases: potential pathological, pharmacological, and toxicological impact.J Biochem Mol Toxicol2003;17:7-23

[27] Stewart MJ,Crabb DW.Distribution of messenger RNAs for aldehyde dehydrogenase 1, aldehyde dehydrogenase 2, and aldehyde dehydrogenase 5 in human tissues.J Investig Med1996;44:42-6

[28] Yanagawa Y,Hsu LC.The transcriptional regulation of human aldehyde dehydrogenase I gene.The structural and functional analysis of the promoter. J Biol Chem1995;270:17521-7

[29] Vasiliou V,Estey T.Role of human aldehyde dehydrogenases in endobiotic and xenobiotic metabolism.Drug Metab Rev2004;36:279-99

[30] Alnouti Y.Tissue distribution, ontogeny, and regulation of aldehyde dehydrogenase (Aldh) enzymes mRNA by prototypical microsomal enzyme inducers in mice.Toxicol Sci2008;101:51-64

[31] Black WJ,Marchitti SA,Tipton KF,Vasiliou V.Human aldehyde dehydrogenase genes: alternatively spliced transcriptional variants and their suggested nomenclature.Pharmacogenet Genomics2009;19:893-902 PMCID:PMC3356695

[32] Koppaka V,Chen Y,Nicolaou KC,Petersen D,Hurley TD.Aldehyde dehydrogenase inhibitors: a comprehensive review of the pharmacology, mechanism of action, substrate specificity, and clinical application.Pharmacol Rev2012;64:520-39 PMCID:PMC3400832

[33] Yokoyama A,Omori T,Matsushita S,Maruyama K.Alcohol and aldehyde dehydrogenase gene polymorphisms and oropharyngolaryngeal, esophageal and stomach cancers in Japanese alcoholics.Carcinogenesis2001;22:433-9

[34] Onenli-Mungan N,Elkay M,Baykal T.Type II hyperprolinemia: a case report.Turk J Pediatr2004;46:167-9

[35] Akaboshi S,Novelletto A,Salomons GS,Jakobs C,Gibson KM.Mutational spectrum of the succinate semialdehyde dehydrogenase (ALDH5A1) gene and functional analysis of 27 novel disease-causing mutations in patients with SSADH deficiency.Hum Mutat2003;22:442-50

[36] Mills PB,Jakobs C,Baxter P,Willemsen MA,Tacke U,Weschke B.Mutations in antiquitin in individuals with pyridoxine-dependent seizures.Nat Med2006;12:307-9

[37] Baumgartner MR,Almashanu S,Obie C,Rabier D,Saudubray JM.Hyperammonemia with reduced ornithine, citrulline, arginine and proline: a new inborn error caused by a mutation in the gene encoding delta(1)-pyrroline-5-carboxylate synthase.Hum Mol Genet2000;9:2853-8

[38] Enomoto N,Takada N.Alcoholic liver disease in heterozygotes of mutant and normal aldehyde dehydrogenase-2 genes.Hepatology1991;13:1071-5

[39] Kamino K,Imagawa M,Yoneda H,Kitamura S,Miki T.Deficiency in mitochondrial aldehyde dehydrogenase increases the risk for late-onset Alzheimer's disease in the Japanese population.Biochem Biophys Res Commun2000;273:192-6

[40] Lohberger B,Stuendl N,Liegl-Atzwanger B,Windhager R.Aldehyde dehydrogenase 1, a potential marker for cancer stem cells in human sarcoma.PLoS One2012;7:e43664 PMCID:PMC3426519

[41] Shimamura M,Matsuse M,Mitsutake N.Analysis of multiple markers for cancer stem-like cells in human thyroid carcinoma cell lines.Endocr J2014;61:481-90

[42] Kunju LP,Toy KA,Sabel MS.EZH2 and ALDH-1 mark breast epithelium at risk for breast cancer development.Mod Pathol2011;24:786-93 PMCID:PMC3106137

[43] Burgos-Ojeda D,Buckanovich RJ.Ovarian cancer stem cell markers: prognostic and therapeutic implications.Cancer Lett2012;322:1-7 PMCID:PMC4431611

[44] Chen Y,Matsumoto A,Thompson DC.Aldehyde dehydrogenase 1B1 (ALDH1B1) is a potential biomarker for human colon cancer.Biochem Biophys Res Commun2011;405:173-9 PMCID:PMC3112362

[45] Pors K.Aldehyde dehydrogenases in cancer: an opportunity for biomarker and drug development?.Drug Discov Today2014;19:1953-63

[46] Rodriguez-Torres M.Aldehyde dehydrogenase as a marker and functional mediator of metastasis in solid tumors.Clin Exp Metastasis2016;33:97-113 PMCID:PMC4740561

[47] Tomita H,Tanaka T.Aldehyde dehydrogenase 1A1 in stem cells and cancer.Oncotarget2016;7:11018-32 PMCID:PMC4905455

[48] Liu Y,Duan JJ,Zhang JF,Zhang X,Bian XW.ALDH1A1 expression correlates with clinicopathologic features and poor prognosis of breast cancer patients: a systematic review and meta-analysis.BMC Cancer2014;14:444 PMCID:PMC4070403

[49] Alamgeer M,Szczepny A,Prodanovic Z,Wainer Z,Schneider-Kolsky M,Wright G.The prognostic significance of aldehyde dehydrogenase 1A1 (ALDH1A1) and CD133 expression in early stage non-small cell lung cancer.Thorax2013;68:1095-104 PMCID:PMC3841805

[50] Kahlert C,Beck J,Mogler C,Dutta S,Koch M.Low expression of aldehyde deyhdrogenase 1A1 (ALDH1A1) is a prognostic marker for poor survival in pancreatic cancer.BMC Cancer2011;11:275 PMCID:PMC3135572

[51] Kim H,Kaygusuz G,Li CD,Brooks JD.The retinoic acid synthesis gene ALDH1a2 is a candidate tumor suppressor in prostate cancer.Cancer Res2005;65:8118-24

[52] Li T,Mei YP,Leng BJ,Stass SA.ALDH1A1 is a marker for malignant prostate stem cells and predictor of prostate cancer patients' outcome.Lab Invest2010;90:234-44 PMCID:PMC3552330

[53] Li XS,Fu XY.ALDH1A1 overexpression is associated with the progression and prognosis in gastric cancer.BMC Cancer2014;14:705 PMCID:PMC4180139

[54] Touma SE,Rubin MA,Gudas LJ.Retinoid metabolism and ALDH1A2 (RALDH2) expression are altered in the transgenic adenocarcinoma mouse prostate model.Biochem Pharmacol2009;78:1127-38 PMCID:PMC2753223

[55] Yang T,Liu Z.Cancer stem cells: constantly evolving and functionally heterogeneous therapeutic targets.Cancer Res2014;74:2922-7 PMCID:PMC4112560

[56] Leach DA.Stromal androgen receptor in prostate cancer development and progression.Cancers (Basel)2017;9:E10 PMCID:PMC5295781

[57] Cunha GR.Stromal-epithelial interactions--I.Induction of prostatic phenotype in urothelium of testicular feminized (Tfm/y) mice. J Steroid Biochem1981;14:1317-24

[58] Donjacour AA.The effect of androgen deprivation on branching morphogenesis in the mouse prostate.Dev Biol1988;128:1-14

[59] Kunju LP,Toy KA,Sabel MS.EZH2 and ALDH-1 mark breast epithelium at risk for breast cancer development.Modern Pathol2011;24:786-93 PMCID:PMC3106137

[60] Orywal K,Werel T.The diagnostic significance of serum alcohol dehydrogenase isoenzymes and aldehyde dehydrogenase activity in urinary bladder cancer patients.Anticancer Res2017;37:3537-41

[61] Yan J,Cutz JC,Tang D.Aldehyde dehydrogenase 3A1 associates with prostate tumorigenesis.Br J Cancer2014;110:2593-603 PMCID:PMC4021532

[62] Le Magnen C,Rentsch CA,Gsponer J,Rieken M,Cecchini MG,Bachmann A,Heberer M.Characterization and clinical relevance of ALDHbright populations in prostate cancer.Clin Cancer Res2013;19:5361-71

[63] Doherty RE,Sisley K.Aldehyde dehydrogenase activity selects for the holoclone phenotype in prostate cancer cells.Biochem Biophys Res Commun2011;414:801-7

[64] van den Hoogen C,Cheung H,Pelger RC.The aldehyde dehydrogenase enzyme 7A1 is functionally involved in prostate cancer bone metastasis.Clin Exp Metastasis2011;28:615-25 PMCID:PMC3198191

[65] Wang S,Bao M,Zhang L,Qin C,Li J,Wang Z.ALDH1A3 correlates with luminal phenotype in prostate cancer.Tumour Biol2017;39:1010428317703652

[66] Casanova-Salas I,Arminan A,Mancarella C,Scotlandi K,Lopez-Guerrero JA.MiR-187 targets the androgen-regulated gene ALDH1A3 in prostate cancer.PLoS One2015;10:e0125576 PMCID:PMC4430273

[67] Trasino SE,Wang TT.Androgen regulation of aldehyde dehydrogenase 1A3 (ALDH1A3) in the androgen-responsive human prostate cancer cell line LNCaP.Exp Biol Med (Maywood)2007;232:762-71

[68] Myers JS,Sang QX.Proteomic upregulation of fatty acid synthase and fatty acid binding protein 5 and identification of cancer- and race-specific pathway associations in human prostate cancer tissues.J Cancer2016;7:1452-64 PMCID:PMC4964129

[69] Casanova-Salas I,Arminan A,Mancarella C,Scotlandi K,Lopez-Guerrero JA.MiR-187 targets the androgen-regulated gene ALDH1A3 in prostate cancer.PLoS One2015;10:e0125576 PMCID:PMC4430273

[70] Lonergan PE.Androgen receptor signaling in prostate cancer development and progression.J Carcinog2011;10:20 PMCID:PMC3162670

[71] Henshall SM,Lee CS,Golovsky D,Delprado W,Grygiel JJ.Altered expression of androgen receptor in the malignant epithelium and adjacent stroma is associated with early relapse in prostate cancer.Cancer Res2001;61:423-7

[72] Ricciardelli C,Buchanan G,Neufing P,Marshall VR,Tilley WD.Androgen receptor levels in prostate cancer epithelial and peritumoral stromal cells identify non-organ confined disease.Prostate2005;63:19-28

[73] Chen CD,Tran C,Chen R,Rosenfeld MG.Molecular determinants of resistance to antiandrogen therapy.Nat Med2004;10:33-9

[74] Ruizeveld de Winter JA,Sleddens HM,Trapman J,Santerse AB,van der Kwast TH.Androgen receptor status in localized and locally progressive hormone refractory human prostate cancer.Am J Pathol1994;144:735-46 PMCID:PMC1887232

[75] Chodak GW,Puy LA,Johnson K.Nuclear localization of androgen receptor in heterogeneous samples of normal, hyperplastic and neoplastic human prostate.J Urol1992;147:798-803

[76] Sadi MV,Barrack ER.Immunohistochemical study of androgen receptors in metastatic prostate cancer.Comparison of receptor content and response to hormonal therapy. Cancer1991;67:3057-64

[77] Feldman BJ.The development of androgen-independent prostate cancer.Nat Rev Cancer2001;1:34-45

[78] Scher HI,Gerald W,Tilley WD.Targeting the androgen receptor: improving outcomes for castration-resistant prostate cancer.Endocr Relat Cancer2004;11:459-76

[79] Scher HI.Biology of progressive, castration-resistant prostate cancer: directed therapies targeting the androgen-receptor signaling axis.J Clin Oncol2005;23:8253-61

[80] Ryan CJ,Lal P,Reuter V,Gerald W.Persistent prostate-specific antigen expression after neoadjuvant androgen depletion: an early predictor of relapse or incomplete androgen suppression.Urology2006;68:834-9

[81] Buchanan G,Coetzee GA.Contribution of the androgen receptor to prostate cancer predisposition and progression.Cancer Metastasis Rev2001;20:207-23

[82] Steinkamp MP,Brogley M,Lapensee EW,Hofer MD,Chinnaiyan A,Pienta KJ.Treatment-dependent androgen receptor mutations in prostate cancer exploit multiple mechanisms to evade therapy.Cancer Res2009;69:4434-42 PMCID:PMC2765801

[83] Locke JA,Lubik AA,Hendy SC,Ettinger SL,Nelson CC.Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer.Cancer Res2008;68:6407-15

[84] Heemers HV.Androgen receptor (AR) coregulators: a diversity of functions converging on and regulating the AR transcriptional complex.Endocr Rev2007;28:778-808

[85] Zhu ML.Androgen receptor and growth factor signaling cross-talk in prostate cancer cells.Endocr Relat Cancer2008;15:841-9 PMCID:PMC2740735

[86] Bergerat JP.Pleiotropic functional properties of androgen receptor mutants in prostate cancer.Hum Mutat2009;30:145-57

[87] Duan JJ,Guo YF,Yu SC.ALDH1A3, a metabolic target for cancer diagnosis and therapy.Int J Cancer2016;139:965-75

[88] van den Hoogen C,Cheung H,Pelger RCM.The aldehyde dehydrogenase enzyme 7A1 is functionally involved in prostate cancer bone metastasis.Clin Exp Metastasis2011;28:615-25 PMCID:PMC3198191

[89] Brocker C,Estey T,Cantore M,Chavakis T,Oppermann U.Aldehyde dehydrogenase 7A1 (ALDH7A1) is a novel enzyme involved in cellular defense against hyperosmotic stress.J Biol Chem2010;285:18452-63 PMCID:PMC2881771

[90] Yang Z,Wu Y,Zhang Y,Jiang Y.Clinical diagnosis, treatment, and ALDH7A1 mutations in pyridoxine-dependent epilepsy in three Chinese infants.PLoS One2014;9:e92803 PMCID:PMC3963937

[91] Scharer G,Vasiliou V,Gallagher RC,Van Hove JL.The genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy due to mutations in ALDH7A1.J Inherit Metab Dis2010;33:571-81 PMCID:PMC3112356

[92] Rose AE,Wang J,Pearlman A,Vega YSdMEC,Christos PJ,Pavlick A,Zavadil J,Hernando E,Osman I.Integrative genomics identifies molecular alterations that challenge the linear model of melanoma progression.Cancer Res2011;71:2561-71 PMCID:PMC3070783

[93] Saw YT,Ng SK,Singh S,Welch WR,Fong WP,Vasiliou V,Ng SW.Characterization of aldehyde dehydrogenase isozymes in ovarian cancer tissues and sphere cultures.BMC Cancer2012;12:329 PMCID:PMC3458927

[94] Giacalone NJ,Eisenberg R,Olson SJ,Carbone DP.ALDH7A1 expression is associated with recurrence in patients with surgically resected non-small-cell lung carcinoma.Future Oncol2013;9:737-45 PMCID:PMC5341386

[95] Milone MR,Bifulco K,Lombardi R,Bruzzese F,Budillon A.Proteomic analysis of zoledronic-acid resistant prostate cancer cells unveils novel pathways characterizing an invasive phenotype.Oncotarget2015;6:5324-41

[96] Chandran UR,Dhir R,Lyons-Weiler M,Michalopoulos G,Monzon FA.Gene expression profiles of prostate cancer reveal involvement of multiple molecular pathways in the metastatic process.BMC Cancer2007;7:64 PMCID:PMC1865555

[97] Kim H,Kaygusuz G,Li C,Brooks JD.The retinoic acid synthesis gene ALDH1a2 is a candidate tumor suppressor in prostate cancer.Cancer Res2005;65:8118-24

[98] Touma SE,Rubin MA,Gudas LJ.Retinoid metabolism and ALDH1A2 (RALDH2) expression are altered in the transgenic adenocarcinoma mouse prostate model.Biochem Pharmacol2009;78:1127-38 PMCID:PMC2753223

[99] Shames DS,Gao B,Lewis CM,Jiang A,Kim YH,Fong KM,Wong M,Nanda R,Gerald W,Shay JW,Minna JD.A genome-wide screen for promoter methylation in lung cancer identifies novel methylation markers for multiple malignancies.PLoS Med2006;3:e486 PMCID:PMC1716188

[100] Collins AT,Hyde C,Maitland NJ.Prospective identification of tumorigenic prostate cancer stem cells.Cancer Res2005;65:10946-51

[101] Brown MD,Hart CA,Ramani VA,Clarke NW.Characterization of benign and malignant prostate epithelial Hoechst 33342 side populations.Prostate2007;67:1384-96

[102] Hurt EM,Klarmann GJ,Farrar WL.CD44+ CD24(-) prostate cells are early cancer progenitor/stem cells that provide a model for patients with poor prognosis.Br J Cancer2008;98:756-65 PMCID:PMC2259168

[103] Goldstein AS,Guo C,Witte ON.Identification of a cell of origin for human prostate cancer.Science2010;329:568-71 PMCID:PMC2917982

[104] Chen YJ,Liao CT,Yen TC,Lu YC,Cheng AJ.Head and neck cancer in the betel quid chewing area: recent advances in molecular carcinogenesis.Cancer Sci2008;99:1507-14

[105] Rajasekhar VK,Gerald W,Scher HI.Tumour-initiating stem-like cells in human prostate cancer exhibit increased NF-kappaB signalling.Nat Commun2011;2:162 PMCID:PMC3105310

[106] Maitland NJ,Polson ES,Collins AT.Prostate cancer stem cells: do they have a basal or luminal phenotype?.Horm Cancer2011;2:47-61

[107] Maitland NJ.Cancer stem cells - a therapeutic target?.Curr Opin Mol Ther2010;12:662-73

[108] Szotek PP,Masiakos PT,Connolly D,Dombkowski D,Maclaughlin DT.Ovarian cancer side population defines cells with stem cell-like characteristics and Mullerian inhibiting substance responsiveness.Proc Natl Acad Sci U S A2006;103:11154-9 PMCID:PMC1544057

[109] Ginestier C,Charafe-Jauffret E,Dutcher J,Jacquemier J,Kleer CG,Schott A,Birnbaum D,Dontu G.ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome.Cell Stem Cell2007;1:555-67 PMCID:PMC2423808

[110] Deng S,Lassus H,Kaur S,Li C,Roby KF,Connolly DC,Montone K,Coukos G.Distinct expression levels and patterns of stem cell marker, aldehyde dehydrogenase isoform 1 (ALDH1), in human epithelial cancers.PLoS One2010;5:e10277 PMCID:PMC2858084

[111] Ucar D,Zucali JR,Scott EW,Gray BA.Aldehyde dehydrogenase activity as a functional marker for lung cancer.Chem Biol Interact2009;178:48-55 PMCID:PMC2976869

[112] Huang EH,Zhang T,Dontu G,Fields JZ,Boman BM.Aldehyde dehydrogenase 1 is a marker for normal and malignant human colonic stem cells (SC) and tracks SC overpopulation during colon tumorigenesis.Cancer Res2009;69:3382-9 PMCID:PMC2789401

[113] Dembinski JL.Characterization and functional analysis of a slow cycling stem cell-like subpopulation in pancreas adenocarcinoma.Clin Exp Metastasis2009;26:611-23 PMCID:PMC2776152

[114] van den Hoogen C,Cheung H,Lippitt JM,Hamdy FC,Thalmann GN,Pelger RC.High aldehyde dehydrogenase activity identifies tumor-initiating and metastasis-initiating cells in human prostate cancer.Cancer Res2010;70:5163-73

[115] Birnie R,Roome C,Droop A,Berry PA,Lewis JL,Maitland NJ.Gene expression profiling of human prostate cancer stem cells reveals a pro-inflammatory phenotype and the importance of extracellular matrix interactions.Genome Biol2008;9:R83 PMCID:PMC2441469

[116] Ma S,Lee TK,Wo JY,Guan XY.Aldehyde dehydrogenase discriminates the CD133 liver cancer stem cell populations.Mol Cancer Res2008;6:1146-53

[117] Cheung AM,Leung JC,Huang H,Liang R.Aldehyde dehydrogenase activity in leukemic blasts defines a subgroup of acute myeloid leukemia with adverse prognosis and superior NOD/SCID engrafting potential.Leukemia2007;21:1423-30

[118] Yan J,Cutz JC,Tang D.Aldehyde dehydrogenase 3A1 associates with prostate tumorigenesis.Br J Cancer2014;110:2593-603 PMCID:PMC4021532

[119] Metzler MA.Enzymatic metabolism of vitamin A in developing vertebrate embryos.Nutrients2016;8:E812 PMCID:PMC5188467

[120] Canete A,Munoz-Chapuli R.Role of vitamin A/retinoic acid in regulation of embryonic and adult hematopoiesis.Nutrients2017;9:E159 PMCID:PMC5331590

[121] Czarnewski P,Parigi SM.Retinoic acid and its role in modulating intestinal innate immunity.Nutrients2017;9:E68 PMCID:PMC5295112

[122] Bono MR,Flores-Santibanez F,Rosemblatt M.Retinoic acid as a modulator of T cell immunity.Nutrients2016;8:E349 PMCID:PMC4924190

[123] Busada JT.The role of retinoic acid (RA) in spermatogonial differentiation.Biol Reprod2016;94:10 PMCID:PMC4809555

[124] Stevison F,Tripathy S.Role of retinoic acid-metabolizing cytochrome P450s, CYP26, in inflammation and cancer.Adv Pharmacol2015;74:373-412 PMCID:PMC4859867

[125] Doldo E,Agostinelli S,Ferlosio A,Passeri D,Orlandi A.Vitamin A, cancer treatment and prevention: the new role of cellular retinol binding proteins.Biomed Res Int2015;2015:624627 PMCID:PMC4387950

[126] Schenk T,Zelent A.Unlocking the potential of retinoic acid in anticancer therapy.Br J Cancer2014;111:2039-45 PMCID:PMC4260020

[127] Napoli JL.Retinol metabolism in LLC-PK1 Cells.Characterization of retinoic acid synthesis by an established mammalian cell line. J Biol Chem1986;261:13592-7

[128] Wang C,Napoli JL.Multiple retinol and retinal dehydrogenases catalyze all-trans-retinoic acid biosynthesis in astrocytes.J Biol Chem2011;286:6542-53 PMCID:PMC3283052

[129] Pasquali D,Eichele G.Abnormal level of retinoic acid in prostate cancer tissues.J Clin Endocrinol Metab1996;81:2186-91

[130] Mic FA,Cuenca AE.Novel retinoic acid generating activities in the neural tube and heart identified by conditional rescue of Raldh2 null mutant mice.Development2002;129:2271-82 PMCID:PMC2833017

[131] Duester G.Involvement of alcohol dehydrogenase, short-chain dehydrogenase/reductase, aldehyde dehydrogenase, and cytochrome P450 in the control of retinoid signaling by activation of retinoic acid synthesis.Biochemistry1996;35:12221-7

[132] Duester G.Retinoic acid synthesis and signaling during early organogenesis.Cell2008;134:921-31 PMCID:PMC2632951

[133] Sima A,Mader S.Kinetic characterization of recombinant mouse retinal dehydrogenase types 3 and 4 for retinal substrates.Biochim Biophys Acta2009;1790:1660-4

[134] Duester G,Molotkov A.Cytosolic retinoid dehydrogenases govern ubiquitous metabolism of retinol to retinaldehyde followed by tissue-specific metabolism to retinoic acid.Chem Biol Interact2003;143-144:201-10

[135] Zhao D,Ivins KJ,Hogan P,Drager UC.Molecular identification of a major retinoic-acid-synthesizing enzyme, a retinaldehyde-specific dehydrogenase.Eur J Biochem1996;240:15-22

[136] Appel B.Retinoids run rampant: multiple roles during spinal cord and motor neuron development.Neuron2003;40:461-4

[137] Elizondo G,Cruz R,Vega L.Retinoic acid modulates retinaldehyde dehydrogenase 1 gene expression through the induction of GADD153-C/EBPbeta interaction.Biochem Pharmacol2009;77:248-57 PMCID:PMC2790144

[138] Delva L,Rochette-Egly C,Balitrand N,Chambon P.Physical and functional interactions between cellular retinoic acid binding protein II and the retinoic acid-dependent nuclear complex.Mol Cell Biol1999;19:7158-67 PMCID:PMC84709

[139] Despouy G,Deshaies S,Mazharian A,Chomienne C.Cyclin D3 is a cofactor of retinoic acid receptors, modulating their activity in the presence of cellular retinoic acid-binding protein II.J Biol Chem2003;278:6355-62

[140] Egea PF,Birck C,Timmins PA.Effects of ligand binding on the association properties and conformation in solution of retinoic acid receptors RXR and RAR.J Mol Biol2001;307:557-76

[141] Glass CK.The coregulator exchange in transcriptional functions of nuclear receptors.Genes Dev2000;14:121-41

[142] McKenna NJ.Combinatorial control of gene expression by nuclear receptors and coregulators.Cell2002;108:465-74

[143] Zhang Y.Transcription regulation by histone methylation: interplay between different covalent modifications of the core histone tails.Genes Dev2001;15:2343-60

[144] Woychik NA.The RNA polymerase II machinery: structure illuminates function.Cell2002;108:453-63

[145] Dilworth FJ.Nuclear receptors coordinate the activities of chromatin remodeling complexes and coactivators to facilitate initiation of transcription.Oncogene2001;20:3047-54

[146] Tsagozis P,Pisa P.All trans-retinoic acid abrogates the pro-tumorigenic phenotype of prostate cancer tumor-associated macrophages.Int Immunopharmacol2014;23:8-13

[147] Fontanelli BA,Teixeira GR,Mendes LO,Kurokawa CS,Favaro WJ,Mello Junior W,Junior AR.Chronic ethanol consumption alters all-trans-retinoic acid concentration and expression of their receptors on the prostate: a possible link between alcoholism and prostate damage.Alcohol Clin Exp Res2013;37:49-56

[148] Hammond LA,Durham J,Burnett RD,Chandraratna RA.Antagonists of retinoic acid receptors (RARs) are potent growth inhibitors of prostate carcinoma cells.Br J Cancer2001;85:453-62 PMCID:PMC2364081

[149] Aboseif SR,Narayan P.Effect of retinoic acid on prostatic development.Prostate1997;31:161-7

[150] Nelson CH,Isoherranen N.Therapeutic potential of the inhibition of the retinoic acid hydroxylases CYP26A1 and CYP26B1 by xenobiotics.Curr Top Med Chem2013;13:1402-28 PMCID:PMC4366427

[151] Sosa MS,Maia AG,Bosch A,Ekpin E,Zheng Y,Morrissey C,Farias EF,Aguirre-Ghiso JA.NR2F1 controls tumour cell dormancy via SOX9- and RARbeta-driven quiescence programmes.Nat Commun2015;6:6170 PMCID:PMC4313575

[152] Roy A,Kim OJ,Lynch S,Kumar D.Multiple roles of RARRES1 in prostate cancer: autophagy induction and angiogenesis inhibition.PLoS One2017;12:e0180344 PMCID:PMC5498036

[153] Oldridge EE,Stower MJ,Mann VM,Pellacani D.Retinoic acid represses invasion and stem cell phenotype by induction of the metastasis suppressors RARRES1 and LXN.Oncogenesis2013;2:e45 PMCID:PMC3641360

[154] Trump DL,Stiff D,Day R,Hofacker J.A phase II trial of all-trans-retinoic acid in hormone-refractory prostate cancer: a clinical trial with detailed pharmacokinetic analysis.Cancer Chemother Pharmacol1997;39:349-56

[155] Kelly WK,Reuter VE,Heston WD,Scher HI.The development of biologic end points in patients treated with differentiation agents: an experience of retinoids in prostate cancer.Clin Cancer Res2000;6:838-46

[156] Nehme A,Sellakumar G,Niedner H,Lin X.Modulation of docetaxel-induced apoptosis and cell cycle arrest by all- trans retinoic acid in prostate cancer cells.Br J Cancer2001;84:1571-6 PMCID:PMC2363662

[157] Qian DZ,Wei Y,van de Geijn F,Nakanishi O,Pili R.In vivo imaging of retinoic acid receptor beta2 transcriptional activation by the histone deacetylase inhibitor MS-275 in retinoid-resistant prostate cancer cells.Prostate2005;64:20-8

[158] Tang XH.Retinoids, retinoic acid receptors, and cancer.Annu Rev Pathol2011;6:345-64

[159] Marcato P,Liu RZ,Bydoun M,Clements D,Mathenge EG,Giacomantonio CA,Godbout R.Aldehyde dehydrogenase 1A3 influences breast cancer progression via differential retinoic acid signaling.Mol Oncol2015;9:17-31 PMCID:PMC5528683

[160] Koenig U,Mildner M,Tschachler E.Aldehyde dehydrogenase 1A3 is transcriptionally activated by all-trans-retinoic acid in human epidermal keratinocytes.Biochem Biophys Res Commun2010;400:207-11

[161] Sullivan KE,Wilson KF.ALDH1A3 in CSCs.Aging (Albany NY)2017;9:1351-2

[162] Sullivan KE,Cerione RA,Wilson KF.The stem cell/cancer stem cell marker ALDH1A3 regulates the expression of the survival factor tissue transglutaminase, in mesenchymal glioma stem cells.Oncotarget2017;8:22325-43 PMCID:PMC5410226

[163] Li Y,Ai W,Zhang L,Wang Y,Ren J,Zhou B,Mai L.Regulation of retinoic acid synthetic enzymes by WT1 and HDAC inhibitors in 293 cells.Int J Mol Med2017;40:661-72 PMCID:PMC5547963

[164] Blum R,Burger PE,Salm SN,Kamb A,Marshall L,Wang X,Moscatelli D.Molecular signatures of prostate stem cells reveal novel signaling pathways and provide insights into prostate cancer.PLoS One2009;4:e5722 PMCID:PMC2684642

[165] Polyak K.Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits.Nat Rev Cancer2009;9:265-73

[166] Thiery JP.Epithelial-mesenchymal transitions in tumour progression.Nat Rev Cancer2002;2:442-54

[167] Yang J.Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis.Dev Cell2008;14:818-29

[168] Tsuji T,Hu GF.Epithelial-mesenchymal transition and cell cooperativity in metastasis.Cancer Res2009;69:7135-9 PMCID:PMC2760965

[169] Mol AJ,Meijer GA,van Moorselaar RJ.New experimental markers for early detection of high-risk prostate cancer: role of cell-cell adhesion and cell migration.J Cancer Res Clin Oncol2007;133:687-95

[170] Jin JK,Gallick GE.Steps in prostate cancer progression that lead to bone metastasis.Int J Cancer2011;128:2545-61 PMCID:PMC3082284

[171] Gravdal K,Haukaas SA.A switch from E-cadherin to N-cadherin expression indicates epithelial to mesenchymal transition and is of strong and independent importance for the progress of prostate cancer.Clin Cancer Res2007;13:7003-11

[172] Umbas R,Aalders TW,Karthaus HF,Debruyne FM.Expression of the cellular adhesion molecule E-cadherin is reduced or absent in high-grade prostate cancer.Cancer Res1992;52:5104-9

[173] Umbas R,Bringuier PP,Karthaus HF,Debruyne FM.Decreased E-cadherin expression is associated with poor prognosis in patients with prostate cancer.Cancer Res1994;54:3929-33

[174] Jaggi M,Baker JJ,Galich A.Aberrant expression of E-cadherin and beta-catenin in human prostate cancer.Urol Oncol2005;23:402-6

[175] Saha B,Imam SS,Naritoku WY,Jones LW.Overexpression of E-cadherin and beta-catenin proteins in metastatic prostate cancer cells in bone.Prostate2008;68:78-84

[176] Verras M.Roles and regulation of Wnt signaling and beta-catenin in prostate cancer.Cancer Letters2006;237:22-32

[177] Gupta S,Sara H,Mirtti T,Rantala J,Nees M.FZD4 as a Mediator of ERG oncogene-induced WNT signaling and epithelial-to-mesenchymal transition in human prostate cancer cells.Cancer Res2010;70:6735-45

[178] Cojoc M,Kurth I,Kunz-Schughart LA,Stakhovsky EA,Simin K,Fuessel S,Wirth MP,Baumann M.Aldehyde dehydrogenase is regulated by beta-catenin/TCF and promotes radioresistance in prostate cancer progenitor cells.Cancer Res2015;75:1482-94

[179] Condello S,Nagdas S,Turek J,Matei D.beta-Catenin-regulated ALDH1A1 is a target in ovarian cancer spheroids.Oncogene2015;34:2297-308 PMCID:PMC4275429

[180] Wikstrom P,Franck-Lissbrant I,Bergh A.Transforming growth factor beta1 is associated with angiogenesis, metastasis, and poor clinical outcome in prostate cancer.Prostate1998;37:19-29

[181] Hellsten R,Dahlman A,Bjartell A.Galiellalactone inhibits stem cell-like ALDH-positive prostate cancer cells.PLoS One2011;6:e22118 PMCID:PMC3133629

[182] Kroon P,Stower MJ,Mann VM,Bhasin D,Li C,Maitland NJ.JAK-STAT blockade inhibits tumor initiation and clonogenic recovery of prostate cancer stem-like cells.Cancer Res2013;73:5288-98

[183] Tanei T,Shimazu K,Tanji Y,Tamaki Y.Association of breast cancer stem cells identified by aldehyde dehydrogenase 1 expression with resistance to sequential Paclitaxel and epirubicin-based chemotherapy for breast cancers.Clin Cancer Res2009;15:4234-41

[184] Sladek NE.Aldehyde dehydrogenase-mediated cellular relative insensitivity to the oxazaphosphorines.Curr Pharm Des1999;5:607-25

[185] Moreb JS,Gray B,Zori R.In vitro selection for K562 cells with higher retrovirally mediated copy number of aldehyde dehydrogenase class-1 and higher resistance to 4-hydroperoxycyclophosphamide.Hum Gene Ther1998;9:611-9

[186] Wulf GG,Kuehnle I,Marini F,Andreeff M.A leukemic stem cell with intrinsic drug efflux capacity in acute myeloid leukemia.Blood2001;98:1166-73

[187] Todaro M,Di Stefano AB,Vermeulen L,Tripodo C,Gulotta G,Stassi G.Colon cancer stem cells dictate tumor growth and resist cell death by production of interleukin-4.Cell Stem Cell2007;1:389-402

[188] Ma S,Zheng BJ,Guan XY.CD133+ HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway.Oncogene2008;27:1749-58

[189] Hermann PC,Herrler T,Ellwart JW,Bruns CJ.Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer.Cell Stem Cell2007;1:313-23

[190] Croker AK.Inhibition of aldehyde dehydrogenase (ALDH) activity reduces chemotherapy and radiation resistance of stem-like ALDHhiCD44(+) human breast cancer cells.Breast Cancer Res Treat2012;133:75-87

[191] Honoki K,Kubo A,Mori T,Tsujiuchi T.Possible involvement of stem-like populations with elevated ALDH1 in sarcomas for chemotherapeutic drug resistance.Oncol Rep2010;24:501-5

[192] Landen CNJr,Katre AA,Nick AM,Miller LD,Jennings NB,Bast RCJr,Lopez-Berestein G.Targeting aldehyde dehydrogenase cancer stem cells in ovarian cancer.Mol Cancer Ther2010;9:3186-99 PMCID:PMC3005138

[193] Kawasoe M,Okawa K,Takeda M,Tsurumi H,Arioka Y,Matsunami H,Saito K.Acquired resistance of leukemic cells to AraC is associated with the upregulation of aldehyde dehydrogenase 1 family member A2.Exp Hematol2013;41:597-603.e2 PMCID:PMC5108046

[194] Lee DH,Song JA,Kang H,Jung SG,An HJ.Proteomic identification of paclitaxel-resistance associated hnRNP A2 and GDI 2 proteins in human ovarian cancer cells.J Proteome Res2010;9:5668-76

[195] Sun QL,Yang XH,Lu J.Comparative proteomic analysis of paclitaxel sensitive A549 lung adenocarcinoma cell line and its resistant counterpart A549-Taxol.J Cancer Res Clin Oncol2011;137:521-32

[196] Barr MP,Hoffmann AC,Thomale J,Fennell DA,O'Leary JJ.Generation and characterisation of cisplatin-resistant non-small cell lung cancer cell lines displaying a stem-like signature.PLoS One2013;8:e54193 PMCID:PMC3547914

[197] Sladek NE,Sreerama L.Cellular levels of aldehyde dehydrogenases (ALDH1A1 and ALDH3A1) as predictors of therapeutic responses to cyclophosphamide-based chemotherapy of breast cancer: a retrospective study.Rational individualization of oxazaphosphorine-based cancer chemotherapeutic regimens. Cancer Chemother Pharmacol2002;49:309-21

[198] Sreerama L.Identification and characterization of a novel class 3 aldehyde dehydrogenase overexpressed in a human breast adenocarcinoma cell line exhibiting oxazaphosphorine-specific acquired resistance.Biochem Pharmacol1993;45:2487-505

[199] Moreb JS,Ostmark B.RNAi-mediated knockdown of aldehyde dehydrogenase class-1A1 and class-3A1 is specific and reveals that each contributes equally to the resistance against 4-hydroperoxycyclophosphamide.Cancer Chemother Pharmacol2007;59:127-36

[200] Parajuli B,Hurley TD.Selective ALDH3A1 inhibition by benzimidazole analogues increase mafosfamide sensitivity in cancer cells.J Med Chem2014;57:449-61 PMCID:PMC3988914

[201] Marcato P,Pan D,Gillis M,Helyer L,Leidal A,Giacomantonio CA.Aldehyde dehydrogenase activity of breast cancer stem cells is primarily due to isoform ALDH1A3 and its expression is predictive of metastasis.Stem Cells2011;29:32-45

[202] Bao S,McLendon RE,Shi Q,Dewhirst MW,Rich JN.Glioma stem cells promote radioresistance by preferential activation of the DNA damage response.Nature2006;444:756-60

[203] Gottesman MM,Bates SE.Multidrug resistance in cancer: role of ATP-dependent transporters.Nat Rev Cancer2002;2:48-58

[204] Kondo T,Taga T.Persistence of a small subpopulation of cancer stem-like cells in the C6 glioma cell line.Proc Natl Acad Sci U S A2004;101:781-6 PMCID:PMC321758

[205] Smith PJ,Chappell SC,Burns PA,Errington RJ.Kinetic analysis of intracellular Hoechst 33342--DNA interactions by flow cytometry: misinterpretation of side population status?.Cytometry A2013;83:161-9

[206] Hilton J.Role of aldehyde dehydrogenase in cyclophosphamide-resistant L1210 leukemia.Cancer Res1984;44:5156-60

[207] Friedman HS,Kaufmann SH,Bullock N,Griffith OW.Cyclophosphamide resistance in medulloblastoma.Cancer Res1992;52:5373-8

[208] Sreerama L.Cellular levels of class 1 and class 3 aldehyde dehydrogenases and certain other drug-metabolizing enzymes in human breast malignancies.Clin Cancer Res1997;3:1901-14

[209] Abdullah LN.Mechanisms of chemoresistance in cancer stem cells.Clin Transl Med2013;2:3 PMCID:PMC3565873

[210] Rodriguez-Torres M.Aldehyde dehydrogenase as a marker and functional mediator of metastasis in solid tumors.Clin Exp Metastasis2016;33:97-113 PMCID:PMC4740561

[211] Januchowski R,Zabel M.The role of aldehyde dehydrogenase (ALDH) in cancer drug resistance.Biomed Pharmacother2013;67:669-80

[212] Di C.Multiple drug resistance due to resistance to stem cells and stem cell treatment progress in cancer (Review).Exp Ther Med2015;9:289-93 PMCID:PMC4280950

[213] Chen YC,Hsu HS,Huang PI,Chen DT,Yung MC,Ku HH,Lo WL.Aldehyde dehydrogenase 1 is a putative marker for cancer stem cells in head and neck squamous cancer.Biochem Biophys Res Commun2009;385:307-13

[214] Vinogradov S.Cancer stem cells and drug resistance: the potential of nanomedicine.Nanomedicine (Lond)2012;7:597-615 PMCID:PMC3376090

[215] Harris AL.Hypoxia--a key regulatory factor in tumour growth.Nat Rev Cancer2002;2:38-47

[216] McKenna DJ,Pors K.Current challenges and opportunities in treating hypoxic prostate tumors.J Cancer Metastasis Treat2018;4:11

[217] Movsas B,Horwitz EM,Greenberg RE,Iyer R.Hypoxic regions exist in human prostate carcinoma.Urology1999;53:11-8

[218] Stewart GD,McLaren DB,Habib FK.The relevance of a hypoxic tumour microenvironment in prostate cancer.BJU International2010;105:8-13

[219] Cojoc M,Kurth I,Kunz-Schughart LA,Stakhovsky EA,Simin K,Fuessel S,Wirth MP,Baumann M.Aldehyde dehydrogenase is regulated by beta-catenin/TCF and promotes radioresistance in prostate cancer progenitor cells.Cancer Res2015;75:1482-94

[220] Mao P,Li J,Li P,Luthra S,Benos PV,Wang M,Cheng SY,Nakano I.Mesenchymal glioma stem cells are maintained by activated glycolytic metabolism involving aldehyde dehydrogenase 1A3.Proc Natl Acad Sci U S A2013;110:8644-9 PMCID:PMC3666732

[221] Li X,Li X,Fan Z,Ji Y,Zhang M,Berge V,Nesland JM.Mitochondrial pyruvate carrier function determines cell stemness and metabolic reprogramming in cancer cells.Oncotarget2017;8:46363-80

[222] Clark DW.Aldehyde dehydrogenases in cancer stem cells: potential as therapeutic targets.Ann Transl Med2016;4:518 PMCID:PMC5233526

[223] Castro Nava A,Peitzsch C,Kurth I,Erdmann K,Vittorio O,Dubrovska A.Development of novel radiochemotherapy approaches targeting prostate tumor progenitor cells using nanohybrids.Int J Cancer2015;137:2492-503

[224] Maitland NJ.Getting closer to prostate cancer in patients - what scientists should want from clinicians.J Cancer Metastasis Treat2017;3:262-70

[225] Chen Y,Thompson DC.Focus on molecules: ALDH1A1: from lens and corneal crystallin to stem cell marker.Exp Eye Res2012;102:105-6 PMCID:PMC3423494

[226] Vasiliou V,Petersen DR.Role of aldehyde dehydrogenases in endogenous and xenobiotic metabolism.Chem Biol Interact2000;129:1-19

[227] Stagos D,Brocker C,Jackson BC,Thompson DC.Aldehyde dehydrogenase 1B1: molecular cloning and characterization of a novel mitochondrial acetaldehyde-metabolizing enzyme.Drug Metab Dispos2010;38:1679-87 PMCID:PMC2957164

[228] Krupenko SA.FDH: an aldehyde dehydrogenase fusion enzyme in folate metabolism.Chem Biol Interact2009;178:84-93 PMCID:PMC2664990

[229] Krupenko NI,Strickland KC,Oleinik NV.ALDH1L2 is the mitochondrial homolog of 10-formyltetrahydrofolate dehydrogenase.J Biol Chem2010;285:23054-61 PMCID:PMC2906299

[230] Matsumoto A.Fundamental properties of aldehyde dehydrogenase 2 (ALDH2) and the importance of the ALDH2 polymorphism.Nihon Eiseigaku Zasshi2016;71:55-68(in Japanese)

[231] Muzio G,Paiuzzi E,Canuto RA.Aldehyde dehydrogenases and cell proliferation.Free Radic Biol Med2012;52:735-46

[232] Holmes RS.Biochemical genetics of opossum aldehyde dehydrogenase 3: evidence for three ALDH3A-like genes and an ALDH3B-like gene.Biochem Genet2010;48:287-303

[233] Kim KJ,Jensen K,Malaspina P,Gibson KM.Succinic semialdehyde dehydrogenase: biochemical-molecular-clinical disease mechanisms, redox regulation, and functional significance.Antioxid Redox Signal2011;15:691-718 PMCID:PMC3125545