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Deregulation of the protein phosphatase 2A, PP2A in cancer: complexity and therapeutic options

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Tumor Biology

Abstract

The complexity of the phosphatase, PP2A, is being unravelled and current research is increasingly providing information on the association of deregulated PP2A function with cancer initiation and progression. It has been reported that decreased activity of PP2A is a recurrent observation in many types of cancer, including colorectal and breast cancer (Baldacchino et al. EPMA J. 5:3, 2014; Cristobal et al. Mol Cancer Ther. 13:938–947, 2014). Since deregulation of PP2A and its regulatory subunits is a common event in cancer, PP2A is a potential target for therapy (Baldacchino et al. EPMA J. 5:3, 2014). In this review, the structural components of the PP2A complex are described, giving an in depth overview of the diversity of regulatory subunits. Regulation of the active PP2A trimeric complex, through phosphorylation and methylation, can be targeted using known compounds, to reactivate the complex. The endogenous inhibitors of the PP2A complex are highly deregulated in cancer, representing cases that are eligible to PP2A-activating drugs. Pharmacological opportunities to target low PP2A activity are available and preclinical data support the efficacy of these drugs, but clinical trials are lacking. We highlight the importance of PP2A deregulation in cancer and the current trends in targeting the phosphatase.

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References

  1. Zhang Q, Claret FX. Phosphatases: the new brakes for cancer development? Enzym Res. 2012;2012:1–11.

    Article  Google Scholar 

  2. Qi Z, Yang W, Liu Y, Cui T, Gao H, et al. Loss of PINK1 function decreases PP2A activity and promotes autophagy in dopaminergic cells and a murine model. Neurochem Int. 2011;59:572–81.

    Article  CAS  PubMed  Google Scholar 

  3. Kloeker S, Reed R, McConnell JL, Chang D, Tran K, et al. Parallel purification of three catalytic subunits of the protein serine/threonine phosphatase 2A family (PP2AC, PP4C, and PP6C) and analysis of the interaction of PP2AC with alpha4 protein. Protein Expr Purif. 2003;31:19–33.

    Article  CAS  PubMed  Google Scholar 

  4. Silverstein AM. Actions of PP2A on the MAP kinase pathway and apoptosis are mediated by distinct regulatory subunits. Proc Natl Acad Sci. 2002;99:4221–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Peyssonnaux C, Eychene A. The Raf/MEK/ERK pathway: new concepts of activation. Biol Cell. 2001;93:53–62.

    Article  CAS  PubMed  Google Scholar 

  6. Sablina A, 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 

  7. Hahn K, Miranda M, Francis VA, Vendrell J, Zorzano A, et al. PP2A regulatory subunit PP2A-B′ counteracts S6K phosphorylation. Cell Metab. 2010;11:438–44.

    Article  CAS  PubMed  Google Scholar 

  8. Margolis SS, Perry JA, Forester CM, Nutt LK, Guo Y, et al. Role for the PP2A/B56delta phosphatase in regulating 14-3-3 release from Cdc25 to control mitosis. Cell. 2006;127:759–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Alvarez-Fernandez M, Halim VA, Aprelia M, Mohammed S, Medema RH. Protein phosphatase 2A (B55) prevents premature activation of forkhead transcription factor FoxM1 by antagonizing cyclin A/cyclin-dependent kinase-mediated phosphorylation. J Biol Chem. 2011;286:33029–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Jin Z, Wallace L, Harper SQ, Yang J. PP2A:B56{epsilon}, a substrate of caspase-3, regulates p53-dependent and p53-independent apoptosis during development. J Biol Chem. 2010;285:34493–502.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Alessi DR, Andjelkovic M, Caudwell B, Cron P, Morrice N, et al. Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J. 1996;15:6541–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Puustinen P, Junttila MR, Vanhatupa S, Sablina AA, Hector ME, 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 

  13. Stebbing J, Lit LC, Zhang H, Darrington RS, Melaiu O, et al. (2013) The regulatory roles of phosphatases in cancer. Oncogene.

  14. Ismail HMS, Myronova O, Tsuchiya Y, Niewiarowski A, Tsaneva I, et al. Identification of the general transcription factor Yin Yang 1 as a novel and specific binding partner for S6 kinase 2. Cell Signal. 2013;25:1054–63.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  16. Baldacchino S, Saliba C, Petroni V, Fenech AG, Borg N, et al. 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 

  17. Cristobal I, Manso R, Rincon R, Carames C, Senin C, et al. PP2A inhibition is a common event in colorectal cancer and its restoration using FTY720 shows promising therapeutic potential. Mol Cancer Ther. 2014;13:938–47.

    Article  CAS  PubMed  Google Scholar 

  18. Seshacharyulu P, Pandey P, Datta K, Batra SK. Phosphatase: PP2A structural importance, regulation and its aberrant expression in cancer. Cancer Lett. 2013;335:9–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ruediger R, Hentz M, Fait J, Mumby M, Walter G. Molecular model of the A subunit of protein phosphatase 2A: interaction with other subunits and tumor antigens. J Virol. 1994;68:123–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Hemmings BA, Adams-Pearson C, Maurer F, Mueller P, Goris J, et al. Alpha- and beta-forms of the 65-kDa subunit of protein phosphatase 2A have a similar 39 amino acid repeating structure. Biochemistry. 1990;29:3166–73.

    Article  CAS  PubMed  Google Scholar 

  21. Janssens V, Goris J, Van Hoof C. PP2A: the expected tumor suppressor. Curr Opin Genet Dev. 2005;15:34–41.

    Article  CAS  PubMed  Google Scholar 

  22. Gu P, Qi X, Zhou Y, Wang Y, Gao X. Generation of Ppp2Ca and Ppp2Cb conditional null alleles in mouse. Genesis. 2012;50:429–36.

    Article  CAS  PubMed  Google Scholar 

  23. Chen J, Martin BL, Brautigan DL. Regulation of protein serine-threonine phosphatase type-2A by tyrosine phosphorylation. Science. 1992;257:1261–4.

    Article  CAS  PubMed  Google Scholar 

  24. Sontag J-M, Nunbhakdi-Craig V, Mitterhuber M, Ogris E, Sontag E. Regulation of protein phosphatase 2A methylation by LCMT1 and PME-1 plays a critical role in differentiation of neuroblastoma cells. J Neurochem. 2010;115:1455–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 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 

  26. Stanevich V, Jiang L, Satyshur KA, Li Y, Jeffrey PD, et al. The structural basis for tight control of PP2A methylation and function by LCMT-1. Mol Cell. 2011;41:331–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. (2013) GeneCards—The human gene compendium.

  28. Gray KA, Daugherty LC, Gordon SM, Seal RL, Wright MW, et al. Genenames.org: the HGNC resources in 2013. Nucleic Acids Res. 2013:41.

  29. Laine A. The role of an oncoprotein cip2a in breast carcinoma. Turku: University of Turku; 2013.

    Google Scholar 

  30. Kong M, Fox CJ, Mu J, Solt L, Xu A, et al. The PP2A-associated protein alpha4 is an essential inhibitor of apoptosis. Science. 2004;306:695–8.

    Article  CAS  PubMed  Google Scholar 

  31. Slupe AM, Merrill RA, Strack S. Determinants for substrate specificity of protein phosphatase 2A. Enzym Res. 2011;2011:1–8.

    Article  Google Scholar 

  32. Xu Y, Xing Y, Chen Y, Chao Y, Lin Z, et al. Structure of the protein phosphatase 2A holoenzyme. Cell. 2006;127:1239–51.

    Article  CAS  PubMed  Google Scholar 

  33. Yu XX, Du X, Moreno CS, Green RE, Ogris E, et al. Methylation of the protein phosphatase 2A catalytic subunit is essential for association of Balpha regulatory subunit but not SG2NA, striatin, or polyomavirus middle tumor antigen. Mol Biol Cell. 2001;12:185–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 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 

  35. Calin GA, Iasio MG, Caprini E, Vorechovsky I, Natali PG, et al. Low frequency of alterations of the α (PPP2R1A) and β (PPP2R1B) isoforms of the subunit A of the serine-threonine phosphatase 2A in human neoplasms. Oncogene. 2000;19:1191–5.

    Article  CAS  PubMed  Google Scholar 

  36. Ruediger R, Ruiz J, Walter G. Human cancer-associated mutations in the A α subunit of protein phosphatase 2A increase lung cancer incidence in A α knock-in and knockout mice. Mol Cell Biol. 2011;31:3832–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Wang SS, Esplin ED, Li JL, Huang L, Evans GA. Alterations of the PPP2R1B gene in human lung and colon cancer. Science. 1998;282:284–7.

    Article  CAS  PubMed  Google Scholar 

  38. Takagi Y, Futamura M, Yamaguchi K, Aoki S, Takahashi T, et al. Alterations of the PPP2R1B gene located at 11q23 in human colorectal cancers. Gut. 2000;47:268–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Chou H-C, Chen C-H, Lee H-S, Lee C-Z, Huang G-T, et al. Alterations of tumour suppressor gene PPP2R1B in hepatocellular carcinoma. Cancer Lett. 2007;253:138–43.

    Article  CAS  PubMed  Google Scholar 

  40. Sablina AA, Chen W, Arroyo JD, Corral L, Hector M, et al. The tumor suppressor PP2A Aβ regulates the RalA GTPase. Cell. 2007;129:969–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Cheng Y, Liu W, Kim S-T, Sun J, Lu L, et al. Evaluation of PPP2R2A as a prostate cancer susceptibility gene: a comprehensive germline and somatic study. Cancer Genet. 2011;204:375–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Niemelä M, Kauko O, Sihto H, Mpindi JP, Nicorici D, et al. CIP2A signature reveals the MYC dependency of CIP2A-regulated phenotypes and its clinical association with breast cancer subtypes. Oncogene. 2012;31:4266–78.

    Article  PubMed  Google Scholar 

  43. Migueleti DLS, Smetana JHC, Nunes HF, Kobarg J, Zanchin NIT. Identification and characterization of an alternatively spliced isoform of the human protein phosphatase 2A catalytic subunit. J Biol Chem. 2011;287:4853–62.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Grech G, Blazquez-Domingo M, Kolbus A, Bakker WJ, Mullner EW, et al. Igbp1 is part of a positive feedback loop in stem cell factor-dependent, selective mRNA translation initiation inhibiting erythroid differentiation. Blood. 2008;112:2750–60.

    Article  CAS  PubMed  Google Scholar 

  45. Neviani P, Santhanam R, Trotta R, Notari M, Blaser BW, et al. The tumor suppressor PP2A is functionally inactivated in blast crisis CML through the inhibitory activity of the BCR/ABL-regulated SET protein. Cancer Cell. 2005;8:355–68.

    Article  CAS  PubMed  Google Scholar 

  46. Markova B, Albers C, Breitenbuecher F, Melo JV, Brümmendorf TH, et al. Novel pathway in Bcr-Abl signal transduction involves Akt-independent, PLC-γ1-driven activation of mTOR/p70S6-kinase pathway. Oncogene. 2009;29:739–51.

    Article  PubMed  Google Scholar 

  47. O’Hare T, Deininger MWN, Eide CA, Clackson T, Druker BJ. Targeting the BCR-ABL signaling pathway in therapy-resistant Philadelphia chromosome-positive leukemia. Clin Cancer Res. 2010;17:212–21.

    Article  PubMed  Google Scholar 

  48. Lucas CM, Harris RJ, Giannoudis A, Copland M, Slupsky JR, et al. Cancerous inhibitor of PP2A (CIP2A) at diagnosis of chronic myeloid leukemia is a critical determinant of disease progression. Blood. 2011;117:6660–8.

    Article  CAS  PubMed  Google Scholar 

  49. Barjesteh van Waalwijk van Doorn-Khosrovani S, Spensberger D, de Knegt Y, Tang M, Lowenberg B, et al. Somatic heterozygous mutations in ETV6 (TEL) and frequent absence of ETV6 protein in acute myeloid leukemia. Oncogene. 2005;24:4129–37.

    Article  PubMed  Google Scholar 

  50. Minakuchi M, Kakazu N, Gorrin-Rivas MJ, Abe T, Copeland TD, et al. Identification and characterization of SEB, a novel protein that binds to the acute undifferentiated leukemia-associated protein SET. Eur J Biochem. 2001;268:1340–51.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  52. Vaarala MH, Väisänen M-R, Ristimäki A. CIP2A expression is increased in prostate cancer. J Exp Clin Cancer Res. 2010;29:136.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Böckelman C, Lassus H, Hemmes A, Leminen A, Westermarck J, et al. Prognostic role of CIP2A expression in serous ovarian cancer. Br J Cancer. 2011;105:989–95.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Teng H-W, Yang S-H, Lin J-K, Chen W-S, Lin T-C, et al. CIP2A is a predictor of poor prognosis in colon cancer. J Gastrointest Surg. 2012;16:1037–47.

    Article  PubMed  Google Scholar 

  55. Come C, Laine A, Chanrion M, Edgren H, Mattila E, et al. CIP2A is associated with human breast cancer aggressivity. Clin Cancer Res. 2009;15:5092–100.

    Article  CAS  PubMed  Google Scholar 

  56. Wang J, Li W, Li L, Yu X, Jia J, et al. CIP2A is over-expressed in acute myeloid leukaemia and associated with HL60 cells proliferation and differentiation. Int J Lab Hematol. 2011;33:290–8.

    Article  CAS  PubMed  Google Scholar 

  57. Mannava S, Omilian AR, Wawrzyniak JA, Fink EE, Zhuang D, et al. PP2A-B56α controls oncogene-induced senescence in normal and tumor human melanocytic cells. Oncogene. 2011;31:1484–92.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Lazar DF, Saltiel AR. Lipid phosphatases as drug discovery targets for type 2 diabetes. Nat Rev Drug Discov. 2006;5:333–42.

    Article  CAS  PubMed  Google Scholar 

  59. Lyon MA, Ducruet AP, Wipf P, Lazo JS. Dual-specificity phosphatases as targets for antineoplastic agents. Nat Rev Drug Discov. 2002;1:961–76.

    Article  CAS  PubMed  Google Scholar 

  60. Tonks NK. Protein tyrosine phosphatases: from genes, to function, to disease. Nat Rev Mol Cell Biol. 2006;7:833–46.

    Article  CAS  PubMed  Google Scholar 

  61. Liu J, Farmer Jr JD, Lane WS, Friedman J, Weissman I, et al. Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell. 1991;66:807–15.

    Article  CAS  PubMed  Google Scholar 

  62. Bachovchin DA, Zuhl AM, Speers AE, Wolfe MR, Weerapana E, 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 

  63. Bachovchin DA, Mohr JT, Speers AE, Wang C, Berlin JM, 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 

  64. Pusey M, Bail S, Xu Y, Buiakova O, Nestor M, et al. (2016) Inhibition of protein methylesterase 1 decreased cancerous phenotypes in endometrial adenocarcinoma cell lines and xenograft tumor models. Tumour Biol.

  65. Madhunapantula SV, Robertson GP. Therapeutic implications of targeting AKT signaling in melanoma. Enzyme Res. 2011;2011:327923.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Hwang YY, Liang RH. An update in management of noncutaneous T-cell lymphomas. Adv Hematol. 2010;2010:424786.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Christensen DJ, Ohkubo N, Oddo J, Van Kanegan MJ, Neil J, et al. Apolipoprotein E and peptide mimetics modulate inflammation by binding the SET protein and activating protein phosphatase 2A. J Immunol. 2011;186:2535–42.

    Article  CAS  PubMed  Google Scholar 

  68. Neviani P, Santhanam R, Oaks JJ, Eiring AM, Notari M, et al. FTY720, a new alternative for treating blast crisis chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphocytic leukemia. J Clin Invest. 2007;117:2408–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Chiba K. FTY720, a new class of immunomodulator, inhibits lymphocyte egress from secondary lymphoid tissues and thymus by agonistic activity at sphingosine 1-phosphate receptors. Pharmacol Ther. 2005;108:308–19.

    Article  CAS  PubMed  Google Scholar 

  70. Pippa R, Dominguez A, Christensen DJ, Moreno-Miralles I, Blanco-Prieto MJ, et al. Effect of FTY720 on the SET-PP2A complex in acute myeloid leukemia; SET binding drugs have antagonistic activity. Leukemia. 2014;28:1915–8.

    Article  CAS  PubMed  Google Scholar 

  71. Cristobal I, Garcia-Orti L, Cirauqui C, Alonso MM, Calasanz MJ, et al. PP2A impaired activity is a common event in acute myeloid leukemia and its activation by forskolin has a potent anti-leukemic effect. Leukemia. 2011;25:606–14.

    Article  CAS  PubMed  Google Scholar 

  72. Azuma H, Takahara S, Horie S, Muto S, Otsuki Y, et al. Induction of apoptosis in human bladder cancer cells in vitro and in vivo caused by FTY720 treatment. J Urol. 2003;169:2372–7.

    Article  CAS  PubMed  Google Scholar 

  73. Zhang N, Qi Y, Wadham C, Wang L, Warren A, et al. FTY720 induces necrotic cell death and autophagy in ovarian cancer cells: a protective role of autophagy. Autophagy. 2010;6:1157–67.

    Article  CAS  PubMed  Google Scholar 

  74. Zheng T, Meng X, Wang J, Chen X, Yin D, et al. PTEN- and p53-mediated apoptosis and cell cycle arrest by FTY720 in gastric cancer cells and nude mice. J Cell Biochem. 2010;111:218–28.

    Article  CAS  PubMed  Google Scholar 

  75. Dumont AG, Reynoso DG, Trent JC. Essential requirement for PP2A inhibition by the oncogenic receptor c-KIT suggests PP2A reactivation as a strategy to treat c-KIT+ cancers—letter. Cancer Res. 2011;71:2403 .author reply 2404

    Article  CAS  PubMed  Google Scholar 

  76. Omar HA, Chou CC, Berman-Booty LD, Ma Y, Hung JH, et al. Antitumor effects of OSU-2S, a nonimmunosuppressive analogue of FTY720, in hepatocellular carcinoma. Hepatology. 2011;53:1943–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Mukhopadhyay A, Saddoughi SA, Song P, Sultan I, Ponnusamy S, et al. Direct interaction between the inhibitor 2 and ceramide via sphingolipid-protein binding is involved in the regulation of protein phosphatase 2A activity and signaling. FASEB J. 2009;23:751–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Switzer CH, Cheng RY, Vitek TM, Christensen DJ, Wink DA, et al. Targeting SET/I(2)PP2A oncoprotein functions as a multi-pathway strategy for cancer therapy. Oncogene. 2011;30:2504–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Tseng LM, Liu CY, Chang KC, Chu PY, Shiau CW, et al. CIP2A is a target of bortezomib in human triple negative breast cancer cells. Breast Cancer Res. 2012;14:R68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Liu Z, Ma L, Wen ZS, Hu Z, Wu FQ, et al. Cancerous inhibitor of PP2A is targeted by natural compound celastrol for degradation in non-small-cell lung cancer. Carcinogenesis. 2014;35:905–14.

    Article  CAS  PubMed  Google Scholar 

  81. Liu Z, Ma L, Wen ZS, Cheng YX, Zhou GB. Ethoxysanguinarine induces inhibitory effects and downregulates CIP2A in lung cancer cells. ACS Med Chem Lett. 2014;5:113–8.

    Article  CAS  PubMed  Google Scholar 

  82. Uzunoglu S, Uslu R, Tobu M, Saydam G, Terzioglu E, et al. Augmentation of methylprednisolone-induced differentiation of myeloid leukemia cells by serine/threonine protein phosphatase inhibitors. Leuk Res. 1999;23:507–12.

    Article  CAS  PubMed  Google Scholar 

  83. Liao Y, Hung MC. A new role of protein phosphatase 2a in adenoviral E1A protein-mediated sensitization to anticancer drug-induced apoptosis in human breast cancer cells. Cancer Res. 2004;64:5938–42.

    Article  CAS  PubMed  Google Scholar 

  84. Switzer CH, Glynn SA, Ridnour LA, Cheng RY, Vitek MP, et al. Nitric oxide and protein phosphatase 2A provide novel therapeutic opportunities in ER-negative breast cancer. Trends Pharmacol Sci. 2011;32:644–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Urbich C, Reissner A, Chavakis E, Dernbach E, Haendeler J, et al. Dephosphorylation of endothelial nitric oxide synthase contributes to the anti-angiogenic effects of endostatin. FASEB J. 2002;16:706–8.

    CAS  PubMed  Google Scholar 

  86. Perrotti D, Neviani P. Protein phosphatase 2A (PP2A), a drugable tumor suppressor in Ph1(+) leukemias. Cancer Metastasis Rev. 2008;27:159–68.

    Article  CAS  PubMed  Google Scholar 

  87. Switzer CH, Ridnour LA, Cheng RY, Sparatore A, Del Soldato P, et al. Dithiolethione compounds inhibit Akt signaling in human breast and lung cancer cells by increasing PP2A activity. Oncogene. 2009;28:3837–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Kar S, Palit S, Ball WB, Das PK. Carnosic acid modulates Akt/IKK/NF-kappaB signaling by PP2A and induces intrinsic and extrinsic pathway mediated apoptosis in human prostate carcinoma PC-3 cells. Apoptosis. 2012;17:735–47.

    Article  CAS  PubMed  Google Scholar 

  89. McClinch K, Avelar R, Callejas D, Kastrinsky D, Ohlmeyer M, Plymate S, et al. Therapeutic reactivation of PP2A for prostate cancer treatment; 2015 Nov 5–9; Boston, MA. Philadelphia (PA): Molecular targets and cancer therapeutics.

  90. Naetar N, Soundarapandian V, Litovchick L, Goguen KL, Sablina AA, et al. PP2A-mediated regulation of Ras signaling in G2 is essential for stable quiescence and normal G1 length. Mol Cell. 2014;54:932–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Hong CS, Ho W, Zhang C, Yang C, Elder JB, et al. LB100, a small molecule inhibitor of PP2A with potent chemo- and radio-sensitizing potential. Cancer Biol Ther. 2015;16:821–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Pathology, Faculty of Medicine & Surgery, Medical School, University of Malta, Msida, MSD2090, Malta

    Godfrey Grech, Shawn Baldacchino, Maria Pia Grixti & Robert Gauci

  2. Centre for Molecular Medicine and Biobanking, University of Malta, Msida, Malta

    Christian Saliba

  3. Department of Anatomy, Faculty of Medicine & Surgery, University of Malta, Msida, Malta

    Vanessa Petroni

  4. Department of Clinical Pharmacology & Therapeutics, Faculty of Medicine & Surgery, University of Malta, Msida, Malta

    Anthony G. Fenech

  5. Department of Physiology and Biochemistry, Faculty of Medicine & Surgery, University of Malta, Msida, Malta

    Christian Scerri

  6. Molecular Genetics Clinic, Mater Dei Hospital, Msida, Malta

    Christian Scerri

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  1. Godfrey Grech
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Godfrey Grech, Shawn Baldacchino and Christian Saliba contributed equally to this work.

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Grech, G., Baldacchino, S., Saliba, C. et al. Deregulation of the protein phosphatase 2A, PP2A in cancer: complexity and therapeutic options. Tumor Biol. 37, 11691–11700 (2016). https://doi.org/10.1007/s13277-016-5145-4

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