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Monoamine oxidase isoenzymes: genes, functions and targets for behavior and cancer therapy

  • Psychiatry and Preclinical Psychiatric Studies - Review Article
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Abstract

Monoamine oxidase (MAO) catalyzes the oxidative deamination of monoamine neurotransmitters and dietary amines. Two pharmacological types with different substrate and inhibitor specificities were reported. Molecular cloning revealed that the two types of MAO were different genes expressed as different proteins with different functions. MAO A and B have identical intron–exon organization derived by duplication of a common ancestral gene thus they are termed isoenzymes. MAO A knockout mice exhibited aggression, the first clear evidence linking genes to behavior. MAO A KO mice exhibited autistic-like behaviors which could be prevented by reducing serotonin levels at an early developmental age (P1–P7) providing potential therapy. MAO B KO mice were non-aggressive and resistant to Parkinsongenic neurotoxin. More recently it was found that MAO A is overexpressed in prostate cancer and correlates with degree of malignancy. The oncogenic mechanism involves a ROS-activated AKT/FOXO1/TWIST1 signaling pathway. Deletion of MAO A reduced prostate cancer stem cells and suppressed invasive adenocarcinoma. MAO A was also overexpressed in classical Hodgkin lymphoma and glioma brain tumors. MAO B was overexpressed in glioma and non-small cell lung cancer. MAO A inhibitors reduce the growth of prostate cancer, drug sensitive and resistant gliomas and classical Hodgkin lymphoma, and enhance standard chemotherapy. Currently, we are developing NIR dye-conjugated clorgyline (MAO A inhibitor) as a novel dual therapeutic/diagnostic agent for cancer. A phase II clinical trial of MAO inhibitor for biochemical recurrent prostate cancer is ongoing. The role of MAO A and B in several cancer types opens new avenues for cancer therapies.

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Fig. 1

(Adapted from Bach et al. 1988; Grimsby et al. 1991)

Fig. 2

(Adapted from Lan et al. 1989a)

Fig. 3

(Adapted from Grimsby et al. 1991)

Fig. 4

(Adapted from Bortolato et al. 2013b)

Fig. 5
Fig. 6

(Adapted from Wu et al. 2014)

Fig. 7

(Adapted from Liao et al. 2018)

Fig. 8

(Adapted from Liao et al. 2018)

Fig. 9

(Adapted from Kushal et al. 2016)

Fig. 10

(Adapted from Wu et al. 2015)

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Abbreviations

AKT:

Protein kinase B

cHL:

Classical Hodgkin lymphoma

EBV:

Epstein–Barr virus

FFPE:

Formalin-fixed paraffin-embedded

FOXO1:

Forkhead box protein O1

GLUT1:

Glucose transporter 1

H2O2 :

Hydrogen peroxide

HIF-1α:

Hypoxia-inducible factor 1-alpha

HRPC:

Hormone refractory prostate cancer

HRS:

Hodgkin Reed–Sternberg

5-HT:

5-Hydroxytryptamine, serotonin

5-HTT:

Serotonin transporter

IAP:

Inhibitor of apoptosis protein

MAO A:

Monoamine oxidase A

MAO B:

Monoamine oxidase B

NED:

Neuroendocrine differentiation

NIR:

Near-infrared

NMI:

NIR dye–MAO A inhibitor conjugate

NRP-1:

Neuropilin-1

OATPs:

Organic anion-transporting polypeptides

pCPA:

p-Chloro-phenylalanine

PHD3:

Prolyl hydroxylase 3

PI3K:

Phosphoinositide 3-kinase

PTSD:

Posttraumatic stress disorder

PSA:

Prostate specific antigen

ROS:

Reactive oxygen species

TMZ:

Temozolomide

TWIST1:

Twist family BHLH transcription factor 1

VEGFA:

Vascular endothelial growth factor A

References

  • Bach AW, Lan NC, Johnson DL, Abell CW, BEmbenek ME, Kwan SW, Seeburg PH, Shih JC (1988) cDNA cloning of human liver monoamine oxidase A and B: molecular basis of differences in enzymatic properties. Proc Natl Acad Sci USA 85:4934–4938

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bortolato M, Shih JC (2011) Behavioral outcomes of monoamine oxidase deficiency: preclinical and clinical evidence. Int Rev Neurobiol 100:13–42

    Article  PubMed  PubMed Central  Google Scholar 

  • Bortolato M, Godar SC, Davarian S, Chen K, Shih JC (2009) Behavioral disinhibition and reduced anxiety-like behaviors in monoamine oxidase B-deficient mice. Neuropsychopharmacology 34:2746–2757

    Article  CAS  PubMed  Google Scholar 

  • Bortolato M, Godar SC, Alzghoul L, Zhang J, Darling RD, Simpson KL, Bini V, Chen K, Wellman CL, Lin RC, Shih JC (2013a) Monoamine oxidase A and A/B knockout mice display autistic-like features. Int J Neuropsychopharmacol 16:869–888

    Article  CAS  PubMed  Google Scholar 

  • Bortolato M, Godar SC, Tambaro S, Devoto P, Chen K, Shih JC (2013b) Early postnatal inhibition of serotonin synthesis results in long-term reductions of perseverative and anxiety-like behaviors, but not aggression, in MAO A-deficient mice. Neuropharmacology 75:223–232

    Article  CAS  PubMed  Google Scholar 

  • Bortolato M, Floris G, Shih JC (2018) From aggression to autism: new perspectives on the behavioral sequela of monoamine oxidase deficiency. J Neural Transm (Vienna). https://doi.org/10.1007/s00702-018-1888-y

    Article  Google Scholar 

  • Brunner HG, Nelen M, Breakenfield XO, Ropers HH, van Oost BA (1993) Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A. Science 262:578–580

    Article  CAS  PubMed  Google Scholar 

  • Camell CD, Sander J, Spadaro O, Lee A, Nguyen KY, Wing A, Goldberg EL, Youm YH, Brown CW, Elsworth J, Rodeheffer MS, Schultze JL, Dixit VD (2017) Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis during ageing. Nature 550:119–123

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cases O, Seif I, Grimsby J, Gaspar P, Chen K, Poumin S, Muller U, Aquet M, Babinet C, Shih JC (1995) Aggressive behavior and altered amounts of brain serotonin and norepinephrine in mice lacking MAO A. Science 268:1763–1766

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen K, Holschneider DP, Wu W, Rebrin I, Shih JC (2004) A spontaneous point mutation produces monoamine oxidase A/B knock-out mice with greatly elevated monoamines and anxiety-like behavior. J Biol Chem 279:39645–39652

    Article  CAS  PubMed  Google Scholar 

  • Chen K, Ou XM, Wu W, Chen G, Shih JC (2005) R1, a novel repressor of the human monoamine oxidase A. J Biol Chem 25:11552–11559

    Article  Google Scholar 

  • Chen K, Rebrin I, Cases O, Seif I, Shih JC (2007) Forebrain specific expression of monoamine oxidase A reduces neurotransmitter levels, restores the brain structure and rescues aggressive behavior in monoamine oxidase A deficient mice. J Biol Chem 282:115–123

    Article  CAS  PubMed  Google Scholar 

  • Deshwal S, Di Sante M, Di Lisa F, Kaludercic N (2017) Emerging role of monoamine oxidase as a therapeutic target for cardiovascular disease. Curr Opin Pharmacol 33:64–69

    Article  CAS  PubMed  Google Scholar 

  • Godar SC, Bortolato M, Castelli MP, Casti A, Casu A, Chen K, Ennas MG, Tambaro S, Shih JC (2014) The aggression and behavioral abnormalities associated with monoamine oxidase A deficiency are rescued by acute inhibition of serotonin reuptake. J Psychaitr Res 56:1–9

    Article  Google Scholar 

  • Gordon RR, Wu M, Huang CY, Harris WP, Sim HG, Lucas JM, Coleman I, Higano CS, Gulati R, True LD, Vessella R, Lange PH, Garzotto M, Beer TM, Nelson PS (2014) Chemotherapy induced monoamine oxidase expression in prostate carcinoma functions as a cytoprotective resistance enzyme and associates with clinical outcomes. PLoS One 9:e104271

    Article  PubMed  PubMed Central  Google Scholar 

  • Grimsby J, Chen K, Wang LJ, lan NC, Shih JC (1991) Human monoamine oxidase A and B genes exhibit identical exon-intron organization. Proc Natl Acad Sci USA 88:3637–3641

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grimsby J, Toth M, Chen K, Kumazawa T, Klaidman L, Adams JD, Karoum F, Gal J, Shih JC (1997) Increased stress response and β B-deficient mice. Nat Genet 17:206–210

    Article  CAS  PubMed  Google Scholar 

  • Gross M, Agus D, Dorff T, Pinski J, Quinn D, Shih JC (2016) Invited submission, a late breaking abstract “Interim analysis of phenelzine (a monoamine oxidase inhibitor) for non-metastatic recurrent prostate cancer”, October 30. Presented at Prostate Cancer Foundation Meeting, San Diego

  • Hare ML (1928) Tyramine oxidase: a new enzyme system in liver. Biochem J 22:968–979

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hintiryan H, Foster NN, Bowman I, Bay M, Song MY, Gou L, Yamashita S, Bienkowski MS, Zingg B, Zhu M, Yang XW, Shih JC, Toga AW, Dong HW (2016) The mouse cortico-striatal projectome. Nat Neurosci 19:1100–1114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Johnston JP (1968) Some observations upon a new inhibitor of monoamine oxidase in brain tissue. Biochem Pharmacol 17:1285–1297

    Article  CAS  PubMed  Google Scholar 

  • Kaludercic N, Mialet-Perez J, Paolocci N, Parini A, Di Lisa F (2014) Monoamine oxidases as sources of oxidants in the heart. J Mol Cell Cardiol 73:34–42

    Article  CAS  PubMed  Google Scholar 

  • Knoll J, Magyar K (1972) Some puzzling pharmacological effects of monoamine oxidase inhibitors. Adv Biochem Psychopharmacol 5:393–408

    CAS  PubMed  Google Scholar 

  • Kushal S, Wang W, Vaikari VP, Kota R, Chen K, Yeh TS, Jhaveri N, Groshen SL, Olenyuk BZ, Chen TC, Hofman FM, Shih JC (2016) Monoamine oxidase A (MAO A) inhibitors decrease glioma progression. Oncotarget 7:13842–13853

    Article  PubMed  PubMed Central  Google Scholar 

  • Lan NC, Chen CH, Shih JC (1989a) Expression of functional human monoamine oxidase A and B cDNAs in mammalian cells. J Neurochem 52:1652–1654

    Article  CAS  PubMed  Google Scholar 

  • Lan NC, Heinzmann C, Gal A, Klisak I, Orth U, Grimsby J, Sparkes RS, Mohandas T, Shih JC (1989b) Human monoamine oxidase A and B genes map to Xp 11.23 and are deleted in a patient with Norrie disease. Genomics 4:552–559

    Article  CAS  PubMed  Google Scholar 

  • Li PC, Siddiqi IN, Mottok A, Loo EY, Wu CH, Cozen W, Steidl C, Shih JC (2017) Monoamine oxidase A is highly expressed in classical Hodgkin lymphoma. J Pathol 243:220–229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liao CP, Lin TP, Li PC, Geary LA, Chen K, Vaikari VP, Wu JB, Lin CH, Gross ME, Shih JC (2018) Loss of MAO A in epithelia inhibits adenocarcinoma development, cell proliferation and cancer stem cells in prostate. Oncogene 37:5175–5190

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lin YC, Chang YT, Campbell M, Lin TP, Pan CC, Lee HC, Shih JC, Chang PC (2017) MAO A-a novel decision maker of apoptosis and autophagy in hormone refractory neuroendocrine prostate cancer cells. Sci Rep 7:46338

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ou XM, Chen K, Shih JC (2004) Dual functions of transcription factors, transforming growth factor-beta-inducible early gene (TIEG)2 and Sp3, are mediated by CACCC element and Sp1 sites of human monoamine (MAO) B gene. J Biol Chem 279:21021–21028

    Article  CAS  PubMed  Google Scholar 

  • Ou XM, Chen K, Shih JC (2006a) Glucocorticoid and androgen activation of monoamine oxidase A are regulated by R1 and SP1. J Biol Chem 281:21512–21525

    Article  CAS  PubMed  Google Scholar 

  • Ou XM, Chen K, Shih J (2006b) Monoamine oxidase A and repressor R1 are involved in apoptotic signaling pathway. Proc Natl Acad Sci USA 103:10923–10928

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Peehl DM, Coram M, Khine H, Reese S, Nolley R, Zhao H (2008) The significance of monoamine oxidase-A expression in high grade prostate cancer. J Urol 180:2206–2211

    Article  PubMed  PubMed Central  Google Scholar 

  • Scott AL, Bortolato M, Chen K, Shih JC (2008) Novel monoamine oxidase A knockout mice with human-like spontaneous mutation. Neuroreport 19:739–743

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sharpe MA, Baskin DS (2016) Monoamine oxidase B levels are highly expressed in human gliomas and are correlated with the expression of HiF-1α and with transcription factors Sp1 and Sp3. Oncotarget 7:3379–3393

    Article  PubMed  Google Scholar 

  • Sharpe MA, Livingston AD, Gist TL, Ghosh P, Han J, Baskin DS (2015) Successful treatment of intracranial glioblastoma xenografts with a monoamine oxidase B-activated pro-drug. EBioMedicine 2:1122–1132

    Article  PubMed  PubMed Central  Google Scholar 

  • Sharpe MA, Raghavan S, Baskin DS (2018) PAM-OBG: a monoamine oxidase B specific prodrug that inhibits MGMT and generates DNA interstrand crosslinks, potentiating temozolomide and chemoradiation therapy in intracranial glioblastoma. Oncotarget 9:23923–23943

    Article  PubMed  PubMed Central  Google Scholar 

  • Shih JC (2004) Cloning, after cloning, knock-out mice, and physiological function of MAO A and B. Shih JC NeuroToxicology 25:21–30

    Article  CAS  PubMed  Google Scholar 

  • Shih JC, Eiduson S (1969) Multiple forms of monoamine oxidase in developing brain. Nature 224:1309–1311

    Article  CAS  PubMed  Google Scholar 

  • Shih JC, Thompson RF (1999c) Monoamine oxidase in neuropsychiatry and behavior. Am J Hum Genet 65:593–598

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shih JC, Chen K, Ridd MJ (1999a) Monoamine oxidase: from genes to behavior. Annu Rev Neurosci 22:197–217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shih JC, Ridd MJ, Chen K, Meehan WP, Kung M-P, Seif I, De Mayer E (1999b) Ketanserin and tetrabenazine abolish aggression in mice lacking monoamine oxidase A. Brain Res 835:104–112

    Article  CAS  PubMed  Google Scholar 

  • Shih JC, Wu JB, Chen K (2011) Transcriptional regulation and multiple functions of MAO genes. J Neural Transm 118:979–986

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Singh C, Bortolato M, Balic N, Godard SC, Scott AL, Chen K, Thompson RF, Shih JC (2013) Cognitive abnormalities and hippocampal alterations in monoamine oxidase A and B knockout mice. Proc Natl Acad Sci 110:12816–12821

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Son B, Jun SY, Seo H, Youn H, Yang HJ, Kim W, Kim HK, Kang C, Youn B (2016) Inhibitory effect of traditional oriental medicine-derived monoamine oxidase B inhibitor on radioresistance of non-small cell lung cancer. Sci Rep 6:21986

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Song MS, Matveychuk D, MacKenzie EM, Duchcherer M, Mousseau DD, Baker GB (2013) An update on amine oxidase inhibitors: multifaceted drugs. Prog Neuropsychopharmacol Biol Psychiatry 44:118–124

    Article  CAS  PubMed  Google Scholar 

  • True L, Coleman I, Hawley S, Huang CY, Gifford D, Coleman R, Beer TM, Gelmann E, Datta M, Mostaghel E, Knudsen B, Lange P, Vessella R, Lin D, Hood L, Nelson PS (2006) A molecular correlate to the Gleason grading system for prostate adenocarcinoma. Proc Natl Acad Sci USA 103:10991–10996

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • White TA, Kwon EM, Fu R, Lucas JM, Ostrander EA, Stanford JL, Nelson PS (2012) The monoamine oxidase A gene promoter repeat and prostate cancer risk. Prostate 72:1622–7162

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wong WK, Chen K, Shih JC (2001) Regulation of human monoamine oxidase B gene by Sp1 and Sp3. Mol Pharmacol 59:852–859

    Article  CAS  PubMed  Google Scholar 

  • Wong WK, Ou X-M, Chen K, Shih JC (2002) Activation of human monoamine oxidase B gene expression by a protein kinase C, MAPK signal transduction pathway involves c-Jun and Egr-1. J Biol Chem 277:22222–22230

    Article  CAS  PubMed  Google Scholar 

  • Wong WK, Chen K, Shih JC (2003) Decreased methylation and transcription repressor Sp3 up-regulated human monoamine oxidase (MAO) B expression during Caco-2 differentiation. J Biol Chem 278:36227–36235

    Article  CAS  PubMed  Google Scholar 

  • Wu JB, Chen K, Li Y, Lau YF, Shih JC (2009a) Regulation of monoamine oxidase A by the SRY gene on the Y chromosome. FASEB J 23:4029–4038

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu JB, Chen K, Ou XM, Shih JC (2009b) Retinoic acid activates monoamine oxidase B promoter in human neuronal cells. J Biol Chem 284:16723–16735

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu JB, Shao C, Li X, Li Q, Hu P, Shi C, Li Y, Chen YT, Yin F, Liao CP, Stiles BL, Zhau HE, Shih JC, Chung LW (2014) Monoamine oxidase A mediates prostate tumorigenesis and cancer metastasis. J Clin Invest 124:2891–2908

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu JB, Lin TP, Gallagher JD, Kushal S, Chung LW, Zhau HE, Olenyuk BZ, Shih JC (2015) Monoamine oxidase A inhibitor-near-infrared dye conjugate reduces prostate tumor growth. J Am Chem Soc 137:2366–2374

    Article  CAS  PubMed  Google Scholar 

  • Xu S, Adisetiyo H, Tamura S, Grande F, Garofalo A, Roy-Burman P, Neamati N (2015) Dual inhibition of survivin and MAO A synergistically impairs growth of PTEN-negative prostate cancer. Br J Cancer 113:242–251

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Youdim MB, Collins GG, Sandler M (1969) Multiple forms of rat brain monoamine oxidase. Nature 223:626–628

    Article  CAS  PubMed  Google Scholar 

  • Zhang Z, Chen K, Shih JC, Teng CT (2006) Estrogen-related receptors-stimulated monoamine oxidase B promoter activity is down-regulated by estrogen receptors. Mol Endocr 20:1547–1561

    Article  CAS  Google Scholar 

  • Zhu QS, Shih JC (1997) An extensive repeat structure down-regulates human monoamine oxidase A promoter activity independent of an initiator-like sequence. J Neurochem 69:1368–1373

    Article  CAS  PubMed  Google Scholar 

  • Zhu QS, Grimsby J, Chen K, Shih JC (1992) Promoter organization and activity of human monoamine oxidase (MAO) A and B genes. J Neurosci 12:4437–4446

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhu QS, Chen K, Shih JC (1994) Bidirectional promoter of human monoamine oxidase A (MAO A) controlled by transcription factor Sp1. J Neurosci 14:7393–7403

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ziegler C, Richter J, Mahr M, Gajewska A, Schiele MA, Gehrmann A, Schmidt B, Lesch KP, Lang T, Helbig-Lang S, Pauli P, Kircher T, Reif A, Rief W, Vossbeck-Elsebusch AN, Arolt V, Wittchen HU, Hamm AO, Deckert J, Domschke K (2016) MAO A gene hypomethylation in panic disorder-reversibility of an epigenetic risk pattern by psychotherapy. Transl Psychiatry 5(6):e773. https://doi.org/10.1038/tp.2016.41

    Article  CAS  Google Scholar 

  • Ziegler C, Wolf C, Schiele MA, Feric Bojic E, Kucukalic S, Sabic Dzananovic E et al (2018) Monoamine oxidase A gene methylation and its role in posttraumatic stress disorder: first evidence from the South Eastern Europe (SEE)-PTSD Study. Int J Neuropsychopharmacol 21:423–432

    Article  PubMed  Google Scholar 

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Acknowledgements

The work presented here was supported by NIH grants including two MERIT awards, grants from USC Trustee Tsai Family Fund, and the Boyd and Elsie Welin Professorship. The invaluable contributions of my long-time collaborator Dr. Kevin Chen are gratefully acknowledged. The contributions of international collaborators, graduate students, postdoctoral fellows, and research associates are deeply appreciated. The editing assistance of Frank Hong and Ronald Irwin is also gratefully acknowledged.

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Authors and Affiliations

  1. Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Ave., Los Angeles, CA, 90089, USA

    Jean C. Shih

  2. Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Jean C. Shih

  3. Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Jean C. Shih

  4. USC-Taiwan Center for Translational Research, University of Southern California, Los Angeles, CA, USA

    Jean C. Shih

  5. College of Pharmacy, Taipei Medical University, Taipei, Taiwan

    Jean C. Shih

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Correspondence to Jean C. Shih.

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Conflict of interest

JCS is an inventor on issued US patents 9,771,625 and 9,675,620 related to MAO inhibitor-based compounds that target prostate and brain cancers.

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Shih, J.C. Monoamine oxidase isoenzymes: genes, functions and targets for behavior and cancer therapy. J Neural Transm 125, 1553–1566 (2018). https://doi.org/10.1007/s00702-018-1927-8

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