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Inhibition of protein methylesterase 1 decreased cancerous phenotypes in endometrial adenocarcinoma cell lines and xenograft tumor models

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Tumor Biology

Abstract

Protein methylesterase 1 (PME-1) promotes cancerous phenotypes through the demethylation and inactivation of protein phosphatase 2A. We previously demonstrated that PME-1 overexpression promotes Akt, ERK, and may promote Wnt signaling and increases tumor burden in a xenograft model of endometrial cancer. Here, we show that covalent PME-1 inhibitors decrease cell proliferation and invasive growth in vitro but have no effect in vivo at the concentrations tested; however, depletion of PME-1 with shRNA in an endometrial cancer xenograft model significantly reduced tumor growth. Thus, discovery of more potent PME-1 inhibitors may be beneficial for the treatment of endometrial cancer.

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References

  1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63:11–30.

    Article  PubMed  Google Scholar 

  2. Wandzioch E, Pusey M, Werda A, Bail S, Bhaskar A, Nestor M, Yang JJ, Rice LM: Pme-1 modulates protein phosphatase 2a activity to promote the malignant phenotype of endometrial cancer cells. Cancer Res 2014

  3. Engelsen IB, Akslen LA, Salvesen HB. Biologic markers in endometrial cancer treatment. APMIS. 2009;117:693–707.

    Article  CAS  PubMed  Google Scholar 

  4. Pusey M, Bail S, Werda A, Rice LM: Protein phosphatase methylesterase 1: A potential therapeutic target and companion diagnostic marker for cancer. Cancer Cell Microenviron 2014;1

  5. Jackson JB, Pallas DC. Circumventing cellular control of PP2a by methylation promotes transformation in an Akt-dependent manner. Neoplasia. 2012;14:585–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Puustinen P, Junttila MR, Vanhatupa S, Sablina AA, Hector ME, Teittinen K, et al. PME-1 protects extracellular signal-regulated kinase pathway activity from protein phosphatase 2A-mediated inactivation in human malignant glioma. Cancer Res. 2009;69:2870–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Lee J, Chen Y, Tolstykh T, Stock J. A specific protein carboxyl methylesterase that demethylates phosphoprotein phosphatase 2A in bovine brain. Proc Natl Acad Sci U S A. 1996;93:6043–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ogris E, Du X, Nelson KC, Mak EK, Yu XX, Lane WS, et al. A protein phosphatase methylesterase (PME-1) is one of several novel proteins stably associating with two inactive mutants of protein phosphatase 2A. J Biol Chem. 1999;274:14382–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Sents W, Ivanova E, Lambrecht C, Haesen D, Janssens V. The biogenesis of active protein phosphatase 2A holoenzymes: a tightly regulated process creating phosphatase specificity. FEBS J. 2013;280:644–61.

    Article  CAS  PubMed  Google Scholar 

  10. Shi Y. Assembly and structure of protein phosphatase 2A. Sci China C Life Sci. 2009;52:135–46.

    Article  CAS  PubMed  Google Scholar 

  11. Virshup DM, Shenolikar S. From promiscuity to precision: protein phosphatases get a makeover. Mol Cell. 2009;33:537–45.

    Article  CAS  PubMed  Google Scholar 

  12. Sents W, Ivanova E, Lambrecht C, Haesen D, Janssens V: The biogenesis of active protein phosphatase 2A holoenzymes: a tightly regulated process creating phosphatase specificity. FEBS J 2012

  13. Longin S, Zwaenepoel K, Louis JV, Dilworth S, Goris J, Janssens V. Selection of protein phosphatase 2A regulatory subunits is mediated by the C terminus of the catalytic subunit. J Biol Chem. 2007;282:26971–80.

    Article  CAS  PubMed  Google Scholar 

  14. Andrabi S, Gjoerup OV, Kean JA, Roberts TM, Schaffhausen B. Protein phosphatase 2A regulates life and death decisions via Akt in a context-dependent manner. Proc Natl Acad Sci U S A. 2007;104:19011–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Arroyo JD, Hahn WC. Involvement of PP2A in viral and cellular transformation. Oncogene. 2005;24:7746–55.

    Article  CAS  PubMed  Google Scholar 

  16. Junttila MR, Li SP, Westermarck J. Phosphatase-mediated crosstalk between MAPK signaling pathways in the regulation of cell survival. FASEB J. 2008;22:954–65.

    Article  CAS  PubMed  Google Scholar 

  17. Arnold HK, Sears RC. A tumor suppressor role for PP2A-B56alpha through negative regulation of c-Myc and other key oncoproteins. Cancer Metastasis Rev. 2008;27:147–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Eichhorn PJ, Creyghton MP, Bernards R. Protein phosphatase 2A regulatory subunits and cancer. Biochim Biophys Acta. 2009;1795:1–15.

    CAS  PubMed  Google Scholar 

  19. Mumby M. PP2A: unveiling a reluctant tumor suppressor. Cell. 2007;130:21–4.

    Article  CAS  PubMed  Google Scholar 

  20. Sablina AA, Hahn WC. The role of PP2A a subunits in tumor suppression. Cell Adhes Migr. 2007;1:140–1.

    Article  Google Scholar 

  21. Junttila MR, Puustinen P, Niemela M, Ahola R, Arnold H, Bottzauw T, et al. CIP2A inhibits PP2A in human malignancies. Cell. 2007;130:51–62.

    Article  CAS  PubMed  Google Scholar 

  22. Sablina AA, Hector M, Colpaert N, Hahn WC. Identification of PP2A complexes and pathways involved in cell transformation. Cancer Res. 2010;70:10474–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Sablina AA, Hahn WC. SV40 small t antigen and PP2A phosphatase in cell transformation. Cancer Metastasis Rev. 2008;27:137–46.

    Article  CAS  PubMed  Google Scholar 

  24. Baldacchino S, Saliba C, Petroni V, Fenech AG, Borg N, Grech G. Deregulation of the phosphatase, PP2A is a common event in breast cancer, predicting sensitivity to FTY720. EPMA J. 2014;5:3.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Junttila MR, Westermarck J. Mechanisms of MYC stabilization in human malignancies. Cell Cycle. 2008;7:592–6.

    Article  CAS  PubMed  Google Scholar 

  26. Khanna A, Okkeri J, Bilgen T, Tiirikka T, Vihinen M, Visakorpi T, et al. ETS1 mediates MEK1/2-dependent overexpression of cancerous inhibitor of protein phosphatase 2A (CIP2a) in human cancer cells. PLoS ONE. 2011;6, e17979.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Pallai R, Bhaskar A, Sodi V, Rice LM: ETS1 and ELK1 transcription factors regulate cancerous inhibitor of protein phosphatase 2A expression in cervical and endometrial carcinoma cells. Transcription 2012;3

  28. Bachovchin DA, Mohr JT, Speers AE, Wang C, Berlin JM, Spicer TP, et al. Academic cross-fertilization by public screening yields a remarkable class of protein phosphatase methylesterase-1 inhibitors. Proc Natl Acad Sci U S A. 2011;108:6811–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Bachovchin DA, Zuhl AM, Speers AE, Wolfe MR, Weerapana E, Brown SJ, et al. Discovery and optimization of sulfonyl acrylonitriles as selective, covalent inhibitors of protein phosphatase methylesterase-1. J Med Chem. 2011;54:5229–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Lee KW, Im JY, Woo JM, Grosso H, Kim YS, Cristovao AC, et al. Neuroprotective and anti-inflammatory properties of a coffee component in the MPTP model of Parkinson’s disease. Neurotherapeutics. 2013;10:143–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Basurto-Islas G, Blanchard J, Tung YC, Fernandez JR, Voronkov M, Stock M, Zhang S, Stock JB, Iqbal K: Therapeutic benefits of a component of coffee in a rat model of Alzheimer’s disease. Neurobiol Aging 2014

  32. Korch C, Spillman MA, Jackson TA, Jacobsen BM, Murphy SK, Lessey BA, et al. DNA profiling analysis of endometrial and ovarian cell lines reveals misidentification, redundancy and contamination. Gynecol Oncol. 2012;127:241–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Lo MC, Aulabaugh A, Jin G, Cowling R, Bard J, Malamas M, et al. Evaluation of fluorescence-based thermal shift assays for hit identification in drug discovery. Anal Biochem. 2004;332:153–9.

    Article  CAS  PubMed  Google Scholar 

  34. Ozsaran AA, Turker S, Dikmen Y, Erhan Y, Itil I, Terek C, et al. P53 staining as a prognostic indicator in endometrial carcinoma. Eur J Gynaecol Oncol. 1999;20:156–9.

    CAS  PubMed  Google Scholar 

  35. Yang J, Phiel C. Functions of b56-containing PP2As in major developmental and cancer signaling pathways. Life Sci. 2010;87:659–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Zhang Q, Claret FX. Phosphatases: the new brakes for cancer development? Enzyme Res. 2012;2012:659649.

    Article  PubMed  Google Scholar 

  37. Kalev P, Sablina AA. Protein phosphatase 2A as a potential target for anticancer therapy. Anticancer Agents Med Chem. 2011;11:38–46.

    Article  CAS  PubMed  Google Scholar 

  38. Leung D, Hardouin C, Boger DL, Cravatt BF. Discovering potent and selective reversible inhibitors of enzymes in complex proteomes. Nat Biotechnol. 2003;21:687–91.

    Article  CAS  PubMed  Google Scholar 

  39. Guterman L. Covalent drugs form long-lived ties. Chem Eng News. 2011;89:19–26.

    Article  Google Scholar 

  40. Xing Y, Li Z, Chen Y, Stock JB, Jeffrey PD, Shi Y. Structural mechanism of demethylation and inactivation of protein phosphatase 2A. Cell. 2008;133:154–63.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We would like to thank Dr. Eli Mordechai for the financial support and express gratitude to Yanfang Li for the compound synthesis. The authors also wish to thank Drs. Maria Webb, Philip Stein, Andrew Cole, Brian McGuiness, Igor Pechik, and Martin Adelson for their helpful discussions.

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Authors and Affiliations

  1. Oncoveda, Cancer Signaling and Cell Cycle Team, Medical Diagnostic Laboratories, LLC, 1000 Waterview Drive, Room 345, Hamilton, NJ, 08691, USA

    Michelle Pusey, Sophie Bail & Lyndi M. Rice

  2. Invivotek, LLC, 16 Black Forest Road, Hamilton, NJ, 08691, USA

    Yan Xu & Olesia Buiakova

  3. Pathology Department, Members of Genesis Biotechnology Group, LLC, Medical Diagnostic Laboratories LLC, 2439 Kuser Road, Hamilton, NJ, 08690, USA

    Mariya Nestor & Jing-Jing Yang

Authors
  1. Michelle Pusey
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  2. Sophie Bail
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  3. Yan Xu
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  4. Olesia Buiakova
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  5. Mariya Nestor
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  6. Jing-Jing Yang
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  7. Lyndi M. Rice
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Corresponding author

Correspondence to Lyndi M. Rice.

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All animal studies were conducted in compliance with Genesis Biotechnology Group, LLC IACUC-approved protocols.

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Pusey, M., Bail, S., Xu, Y. et al. Inhibition of protein methylesterase 1 decreased cancerous phenotypes in endometrial adenocarcinoma cell lines and xenograft tumor models. Tumor Biol. 37, 11835–11842 (2016). https://doi.org/10.1007/s13277-016-5036-8

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  • DOI: https://doi.org/10.1007/s13277-016-5036-8

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