Article | Published:

Loss of MAOA in epithelia inhibits adenocarcinoma development, cell proliferation and cancer stem cells in prostate

Oncogenevolume 37pages51755190 (2018) | Download Citation

Abstract

Monoamine oxidase A (MAOA) is a mitochondrial enzyme, which degrades monoamine neurotransmitters and dietary amines and produces H2O2. Recent studies have shown increased MAOA expression in prostate cancer (PCa), glioma, and classical Hodgkin lymphoma. However, the biological function of MAOA in cancer development remains unknown. In this study, we investigated the role of MAOA in the development of prostate adenocarcinoma by creating a prostate-specific Pten/MAOA knockout (KO) mouse model, in which MAOA-floxP mouse was crossed with the conditional Pten KO PCa mouse that develops invasive PCa. In contrast to Pten KO mice, age-matched Pten/MAOA KO mice exhibited a significant decrease in both prostate size and the incidence of invasive cancer. We observed a significant decline in AKT phosphorylation and Ki67 expression in Pten/MAOA KO mice, which reduced epithelial cell growth and proliferation. As cancer stem cells (CSCs) are required for tumor initiation and growth, we investigated expression of OCT4 and NANOG in the setting of decreased MAOA expression. We found that both OCT4 and NANOG were significantly attenuated in the prostate epithelia of Pten/MAOA KO mice compared to Pten KO mice, which was confirmed with targeted knockdown of MAOA with a short-hairpin(sh) vector targeting MAOA compared to cells transfected with a control vector. Expression of other markers associated with the a stem cell phenotype, including CD44, α2β1, and CD133 as well as HIF-1α+CD44+ stem cells were all decreased in shMAOA PCa cells compared with empty vector-transfected control cells. We also found spheroid formation ability in PCa cells was decreased when endogenous MAOA was suppressed by siRNA or MAOA inhibitor clorgyline in a colony formation assay. Using the TCGA database, elevated MAOA expression was associated with reduced Pten levels in high Gleason grade in patient samples. Further, we found that Pten-positive PCa cells were more resistant to clorgyline treatments than Pten-null cells in tumorigenicity and stemness. Taken together, these studies suggest that MAOA expression promotes PCa development by increasing cell proliferation and CSCs and highlights the potential use of MAOA inhibitors for the treatment of PCa.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

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

  2. 2.

    Singh C, Bortolato M, Bali N, Godar SC, Scott AL, Chen K, et al. Cognitive abnormalities and hippocampal alterations in monoamine oxidase A and B knockout mice. Proc Natl Acad Sci USA. 2013;110:12816–21.

  3. 3.

    Bach AW, Lan NC, Johnson DL, Abell CW, Bembenek ME, Kwan SW, et al. cDNA cloning of human liver monoamine oxidase A and B: molecular basis of differences in enzymatic properties. Proc Natl Acad Sci USA. 1988;85:4934–8.

  4. 4.

    True L, Coleman I, Hawley S, Huang CY, Gifford D, Coleman R, et al. A molecular correlate to the Gleason grading system for prostate adenocarcinoma. Proc Natl Acad Sci USA. 2006;103:10991–6.

  5. 5.

    Peehl DM, Coram M, Khine H, Reese S, Nolley R, Zhao H. The significance of monoamine oxidase-A expression in high grade prostate cancer. J Urol. 2008;180:2206–11.

  6. 6.

    Wu JB, Shao C, Li X, Li Q, Hu P, Shi C, et al. Monoamine oxidase A mediates prostate tumorigenesis and cancer metastasis. J Clin Investig. 2014;124:2891–908.

  7. 7.

    Wu JB, Lin TP, Gallagher JD, Kushal S, Chung LW, Zhau HE, et al. Monoamine oxidase A inhibitor-near-infrared dye conjugate reduces prostate tumor growth. J Am Chem Soc. 2015;137:2366–74.

  8. 8.

    Kushal S, Wang W, Vaikari VP, Kota R, Chen K, Yeh TS, et al. Monoamine oxidase A (MAO A) inhibitors decrease glioma progression. Oncotarget. 2016;7:13842–53.

  9. 9.

    Li PC, Siddiqi IN, Mottok A, Loo EY, Wu CH, Cozen W, et al. Monoamine oxidase A is highly expressed in classical Hodgkin lymphoma. J Pathol. 2017;243:220–9.

  10. 10.

    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA: A Cancer J Clin. 2017;67:7–30.

  11. 11.

    Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science. 1997;275:1943–7.

  12. 12.

    Chalhoub N, Baker SJ. PTEN and the PI3-kinase pathway in cancer. Annu Rev Pathol. 2009;4:127–50.

  13. 13.

    Wu X, Wu J, Huang J, Powell WC, Zhang J, Matusik RJ, et al. Generation of a prostate epithelial cell-specific Cre transgenic mouse model for tissue-specific gene ablation. Mech Dev. 2001;101:61–9.

  14. 14.

    Wang S, Gao J, Lei Q, Rozengurt N, Pritchard C, Jiao J, et al. Prostate-specific deletion of the murine Pten tumor suppressor gene leads to metastatic prostate cancer. Cancer Cell. 2003;4:209–21.

  15. 15.

    Fu Y, Wey S, Wang M, Ye R, Liao CP, Roy-Burman P, et al. Pten null prostate tumorigenesis and AKT activation are blocked by targeted knockout of ER chaperone GRP78/BiP in prostate epithelium. Proc Natl Acad Sci USA. 2008;105:19444–9.

  16. 16.

    Adisetiyo H, Liang M, Liao CP, Aycock-Williams A, Cohen MB, Xu S, et al. Loss of survivin in the prostate epithelium impedes carcinogenesis in a mouse model of prostate adenocarcinoma. PLoS ONE. 2013;8:e69484.

  17. 17.

    Gottowik J, Cesura AM, Malherbe P, Lang G, Da Prada M. Characterisation of wild-type and mutant forms of human monoamine oxidase A and B expressed in a mammalian cell line. FEBS Lett. 1993;317:152–6.

  18. 18.

    Ma J, Ito A. Tyrosine residues near the FAD binding site are critical for FAD binding and for the maintenance of the stable and active conformation of rat monoamine oxidase A. J Biochem. 2002;131:107–11.

  19. 19.

    Bortolato M, Chen K, Godar SC, Chen G, Wu W, Rebrin I, et al. Social deficits and perseverative behaviors, but not overt aggression, in MAO-A hypomorphic mice. Neuropsychopharmacology. 2011;36:2674–88.

  20. 20.

    Dillon LM, Miller TW. Therapeutic targeting of cancers with loss of PTEN function. Curr Drug Targets. 2014;15:65–79.

  21. 21.

    Tuominen VJ, Ruotoistenmaki S, Viitanen A, Jumppanen M, Isola J. ImmunoRatio: a publicly available web application for quantitative image analysis of estrogen receptor (ER), progesterone receptor (PR), and Ki-67. Breast Cancer Res. 2010;12:R56.

  22. 22.

    Dubrovska A, Kim S, Salamone RJ, Walker JR, Maira SM, Garcia-Echeverria C, et al. The role of PTEN/Akt/PI3K signaling in the maintenance and viability of prostate cancer stem-like cell populations. Proc Natl Acad Sci USA. 2009;106:268–73.

  23. 23.

    Sahlberg SH, Spiegelberg D, Glimelius B, Stenerlow B, Nestor M. Evaluation of cancer stem cell markers CD133, CD44, CD24: association with AKT isoforms and radiation resistance in colon cancer cells. PLoS ONE. 2014;9:e94621.

  24. 24.

    Dawood S, Austin L, Cristofanilli M. Cancer stem cells: implications for cancer therapy. Oncology (Williston Park). 2014;28:1101–7.

  25. 25.

    Collins AT, Berry PA, Hyde C, Stower MJ, Maitland NJ. Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res. 2005;65:10946–51.

  26. 26.

    Al-Hajj M, Becker MW, Wicha M, Weissman I, Clarke MF. Therapeutic implications of cancer stem cells. Curr Opin Genet Dev. 2004;14:43–7.

  27. 27.

    Tan BT, Park CY, Ailles LE, Weissman IL. The cancer stem cell hypothesis: a work in progress. Lab Investig. 2006;86:1203–7.

  28. 28.

    van den Berg DL, Snoek T, Mullin NP, Yates A, Bezstarosti K, Demmers J, et al. An Oct4-centered protein interaction network in embryonic stem cells. Cell Stem Cell. 2010;6:369–81.

  29. 29.

    Vlietstra RJ, van Alewijk DC, Hermans KG, van Steenbrugge GJ, Trapman J. Frequent inactivation of PTEN in prostate cancer cell lines and xenografts. Cancer Res. 1998;58:2720–3.

  30. 30.

    Takubo K, Goda N, Yamada W, Iriuchishima H, Ikeda E, Kubota Y, et al. Regulation of the HIF-1alpha level is essential for hematopoietic stem cells. Cell Stem Cell. 2010;7:391–402.

  31. 31.

    Forristal CE, Nowlan B, Jacobsen RN, Barbier V, Walkinshaw G, Walkley CR, et al. HIF-1alpha is required for hematopoietic stem cell mobilization and 4-prolyl hydroxylase inhibitors enhance mobilization by stabilizing HIF-1alpha. Leukemia. 2015;29:1366–78.

  32. 32.

    Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2:401–4.

  33. 33.

    Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6:pl1.

  34. 34.

    Epstein JI, Zelefsky MJ, Sjoberg DD, Nelson JB, Egevad L, Magi-Galluzzi C, et al. A contemporary prostate cancer grading system: a validated alternative to the Gleason score. Eur Urol. 2016;69:428–35.

  35. 35.

    Oliveira DS, Dzinic S, Bonfil AI, Saliganan AD, Sheng S, Bonfil RD. The mouse prostate: a basic anatomical and histological guideline. Bosn J Basic Med Sci. 2016;16:8–13.

  36. 36.

    Liao CP, Zhong C, Saribekyan G, Bading J, Park R, Conti PS, et al. Mouse models of prostate adenocarcinoma with the capacity to monitor spontaneous carcinogenesis by bioluminescence or fluorescence. Cancer Res. 2007;67:7525–33.

  37. 37.

    Sun H, Lesche R, Li DM, Liliental J, Zhang H, Gao J, et al. PTEN modulates cell cycle progression and cell survival by regulating phosphatidylinositol 3,4,5,-trisphosphate and Akt/protein kinase B signaling pathway. Proc Natl Acad Sci USA. 1999;96:6199–204.

  38. 38.

    Alimonti A, Carracedo A, Clohessy JG, Trotman LC, Nardella C, Egia A, et al. Subtle variations in Pten dose determine cancer susceptibility. Nat Genet. 2010;42:454–8.

  39. 39.

    Gu G, Yuan J, Wills M, Kasper S. Prostate cancer cells with stem cell characteristics reconstitute the original human tumor in vivo. Cancer Res. 2007;67:4807–15.

  40. 40.

    Lawson DA, Xin L, Lukacs R, Xu Q, Cheng D, Witte ON. Prostate stem cells and prostate cancer. Cold Spring Harb Symp Quant Biol. 2005;70:187–96.

  41. 41.

    Nikitin AY, Matoso A, Roy-Burman P. Prostate stem cells and cancer. Histol Histopathol. 2007;22:1043–9.

  42. 42.

    Pfeiffer MJ, Schalken JA. Stem cell characteristics in prostate cancer cell lines. Eur Urol. 2010;57:246–54.

  43. 43.

    Liao CP, Adisetiyo H, Liang M, Roy-Burman P. Cancer-associated fibroblasts enhance the gland-forming capability of prostate cancer stem cells. Cancer Res. 2010;70:7294–303.

  44. 44.

    Liao CP, Adisetiyo H, Liang M, Roy-Burman P. Cancer stem cells and microenvironment in prostate cancer progression. Horm Cancer. 2010;1:297–305.

  45. 45.

    Adisetiyo H, Liang M, Liao CP, Jeong JH, Cohen MB, Roy-Burman P, et al. Dependence of castration-resistant prostate cancer (CRPC) stem cells on CRPC-associated fibroblasts. J Cell Physiol. 2014;229:1170–6.

  46. 46.

    Ting MC, Liao CP, Yan C, Jia L, Groshen S, Frenkel B, et al. An enhancer from the 8q24 prostate cancer risk region is sufficient to direct reporter gene expression to a subset of prostate stem-like epithelial cells in transgenic mice. Dis Models Mech. 2012;5:366–74.

  47. 47.

    Goldstein AS, Huang J, Guo C, Garraway IP, Witte ON. Identification of a cell of origin for human prostate cancer. Science. 2010;329:568–71.

  48. 48.

    Leong KG, Wang BE, Johnson L, Gao WQ. Generation of a prostate from a single adult stem cell. Nature. 2008;456:804–8.

  49. 49.

    Xu S, Adisetiyo H, Tamura S, Grande F, Garofalo A, Roy-Burman P, et al. Dual inhibition of survivin and MAOA synergistically impairs growth of PTEN-negative prostate cancer. British Journal of Cancer. 2015;113:242–51.

  50. 50.

    The Cancer Genome Atlas Research Network. The molecular taxonomy of primary prostate cancer. Cell. 2015;163:1011–25..

Download references

Acknowledgements

We would like to thank Dr. Pradip Roy-Burman for providing the conditional Pten deletion mouse model and for helpful technical discussions, Bin Qian (Department of Pharmacology and Pharmaceutical Sciences, University of Southern California) for technical assistance, F. Hong for critically reading the manuscript, and all members of the Jean C. Shih Laboratory and the Center for Apply Molecular Medicine at USC for assistance in various aspects of this work.

Funding

This work was supported by the Department of Defense Prostate Cancer Research Program grant W81XWH-12-1-0282, the Daniel Tsai Family Fund, and the Boyd and Elsie Welin Professorship (to JCS). The content is solely the responsibility of the authors and does not necessarily represent the official views of the Department of Defense or other funding agency.

Author information

Author notes

  1. These authors contributed equally: Chun-Peng Liao, Tzu-Ping Lin, Pei-Chuan Li.

Affiliations

  1. Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, 90089-9121, USA

    • Chun-Peng Liao
    • , Tzu-Ping Lin
    • , Pei-Chuan Li
    • , Lauren A. Geary
    • , Kevin Chen
    • , Vijaya Pooja Vaikari
    •  & Jean C. Shih
  2. USC-Taiwan Center for Translation Research, University of Southern California, Los Angeles, CA, 90089-9121, USA

    • Chun-Peng Liao
    • , Tzu-Ping Lin
    • , Pei-Chuan Li
    • , Lauren A. Geary
    • , Kevin Chen
    • , Vijaya Pooja Vaikari
    •  & Jean C. Shih
  3. Lawrence J. Ellison Institute for Transformative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033-9075, USA

    • Chun-Peng Liao
    •  & Mitchell E. Gross
  4. Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, WA, 11221, Taiwan

    • Tzu-Ping Lin
    •  & Chi-Hung Lin
  5. Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Spokane, 99210-1495, USA

    • Jason Boyang Wu
  6. Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, 90089-9176, CA, USA

    • Mitchell E. Gross
    •  & Jean C. Shih
  7. Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90089-9037, USA

    • Jean C. Shih
  8. College of Pharmacy, Taipei Medical University, Taipei, 11031, Taiwan

    • Jean C. Shih

Authors

  1. Search for Chun-Peng Liao in:

  2. Search for Tzu-Ping Lin in:

  3. Search for Pei-Chuan Li in:

  4. Search for Lauren A. Geary in:

  5. Search for Kevin Chen in:

  6. Search for Vijaya Pooja Vaikari in:

  7. Search for Jason Boyang Wu in:

  8. Search for Chi-Hung Lin in:

  9. Search for Mitchell E. Gross in:

  10. Search for Jean C. Shih in:

Conflict of interest

The authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Jean C. Shih.

Electronic supplementary material

About this article

Publication history

Received

Revised

Accepted

Published

Issue Date

DOI

https://doi.org/10.1038/s41388-018-0325-x

Further reading