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Understanding the Tumor Suppressor PTEN in Chronic Alcoholism and Hepatocellular Carcinoma

  • Colin T. Shearn
  • Dennis R. Petersen
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 815)

Abstract

The tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a phosphatidylinositol (PtdIns) phosphatase that regulates Akt activation via PtdIns 3 kinase. Changes in PTEN expression and/or activity have been identified in a variety of chronic hepatocellular disorders including obesity, NAFLD, NASH, and alcoholism. In cancer biology, PTEN is frequently mutated or deleted in a wide variety of tumors. Mutations, decreased promoter activity, and decreased expression in PTEN are frequently identified in patients with hepatocellular carcinoma. While the majority of research on PTEN concerns obesity and NASH, PTEN clearly has a role in hepatic insulin sensitivity and in the development of steatosis during chronic alcoholism. Yet, in chronic alcoholics and HCC, very little is known concerning PTEN mutation/deletion or low PTEN expression. This review is focused on an overview of the current knowledge on molecular mechanisms of dysregulation of PTEN expression/activity in the liver and their relationship to development of ethanol-induced hepatocellular damage and cancer.

Keywords

PTEN Chronic ethanol Fatty acid synthesis Posttranslational modification Oxidative stress Hepatic steatosis 

Notes

Grants and Funding

This research was funded by the following grants from the National Institutes of Health; 5F32AA018613-03 CTS.

References

  1. 1.
    De Minicis S, Brenner DA (2008) Oxidative stress in alcoholic liver disease: role of NADPH oxidase complex. J Gastroenterol Hepatol 23(Suppl 1):S98–S103PubMedCrossRefGoogle Scholar
  2. 2.
    Rehm J, Mathers C, Popova S, Thavorncharoensap M, Teerawattananon Y, Patra J (2009) Global burden of disease and injury and economic cost attributable to alcohol use and alcohol-use disorders. Lancet 373(9682):2223–2233PubMedCrossRefGoogle Scholar
  3. 3.
    Beier JI, McClain CJ (2010) Mechanisms and cell signaling in alcoholic liver disease. Biol Chem 391(11):1249–1264PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Kochanek KD, Murphy SL, Anderson RN, Scott C (2004) Deaths: final data for 2002. Natl Vital Stat Rep 53(5):1–115PubMedGoogle Scholar
  5. 5.
    Mohapatra S, Patra J, Popova S, Duhig A, Rehm J (2009) Social cost of heavy drinking and alcohol dependence in high-income countries. Int J Public Health 55(3):149–157PubMedCrossRefGoogle Scholar
  6. 6.
    Ascha MS, Hanouneh IA, Lopez R, Tamimi TA, Feldstein AF, Zein NN (2010) The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology 51(6):1972–1978PubMedCrossRefGoogle Scholar
  7. 7.
    Koike K (2013) The oncogenic role of hepatitis C virus. Recent Results Cancer Res 193:97–111CrossRefGoogle Scholar
  8. 8.
    Mathurin P (2012) EASL clinical practical guidelines: management of alcoholic liver disease. J Hepatol 57(2):399–420CrossRefGoogle Scholar
  9. 9.
    Liew CT (1990) The clinicopathological spectrum of alcoholic liver disease—an autopsy survey of 441 cases. Changgeng Yi Xue Za Zhi 13(2):72–85PubMedGoogle Scholar
  10. 10.
    Davis GL, Dempster J, Meler JD, Orr DW, Walberg MW, Brown B, Berger BD, O’Connor JK, Goldstein RM (2008) Hepatocellular carcinoma: management of an increasingly common problem. Proc (Bayl Univ Med Cent) 21(3):266–280Google Scholar
  11. 11.
    Di Cristofano A, Pandolfi PP (2000) The multiple roles of PTEN in tumor suppression. Cell 100:387–390PubMedCrossRefGoogle Scholar
  12. 12.
    Cotler SJ, Hay N, Xie H, Chen ML, Xu PZ, Layden TJ, Guzman G (2008) Immunohistochemical expression of components of the Akt-mTORC1 pathway is associated with hepatocellular carcinoma in patients with chronic liver disease. Dig Dis Sci 53(3):844–849PubMedCrossRefGoogle Scholar
  13. 13.
    Sze KM, Wong KL, Chu GK, Lee JM, Yau TO, Ng IO (2011) Loss of phosphatase and tensin homolog enhances cell invasion and migration through AKT/Sp-1 transcription factor/matrix metalloproteinase 2 activation in hepatocellular carcinoma and has clinicopathologic significance. Hepatology 53(5):1558–1569PubMedCrossRefGoogle Scholar
  14. 14.
    Wang L, Wang WL, Zhang Y, Guo SP, Zhang J, Li QL (2007) Epigenetic and genetic alterations of PTEN in hepatocellular carcinoma. Hepatol Res 37(5):389–396PubMedCrossRefGoogle Scholar
  15. 15.
    Whittaker S, Marais R, Zhu AX (2010) The role of signaling pathways in the development and treatment of hepatocellular carcinoma. Oncogene 29(36):4989–5005PubMedCrossRefGoogle Scholar
  16. 16.
    Wu SK, Wang BJ, Yang Y, Feng XH, Zhao XP, Yang DL (2007) Expression of PTEN, PPM1A and P-Smad2 in hepatocellular carcinomas and adjacent liver tissues. World J Gastroenterol 13(34):4554–4559PubMedGoogle Scholar
  17. 17.
    Boyault S, Rickman DS, de Reynies A, Balabaud C, Rebouissou S, Jeannot E, Herault A, Saric J, Belghiti J, Franco D, Bioulac-Sage P, Laurent-Puig P, Zucman-Rossi J (2007) Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. Hepatology 45(1):42–52PubMedCrossRefGoogle Scholar
  18. 18.
    Sugihara T, Mandai M, Koda M, Matono T, Nagahara T, Ueki M, Murawaki Y (2011) Cowden syndrome complicated with hepatocellular carcinoma possibly originating from non-alcoholic steatohepatitis (NASH). Hepatol Res 41(2):189–193PubMedCrossRefGoogle Scholar
  19. 19.
    Krycer JR, Sharpe LJ, Luu W, Brown AJ (2010) The Akt-SREBP nexus: cell signaling meets lipid metabolism. Trends Endocrinol Metab 21(5):268–276PubMedCrossRefGoogle Scholar
  20. 20.
    Marte BM, Downward J (1997) PKB/Akt: connecting phosphoinositide 3-kinase to cell survival and beyond. Trends Biochem Sci 22(9):355–358PubMedCrossRefGoogle Scholar
  21. 21.
    Leavens KF, Easton RM, Shulman GI, Previs SF, Birnbaum MJ (2009) Akt2 is required for hepatic lipid accumulation in models of insulin resistance. Cell Metab 10(5):405–418PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Xu X, Sakon M, Nagano H, Hiraoka N, Yamamoto H, Hayashi N, Dono K, Nakamori S, Umeshita K, Ito Y, Matsuura N, Monden M (2004) Akt2 expression correlates with prognosis of human hepatocellular carcinoma. Oncol Rep 11(1):25–32PubMedGoogle Scholar
  23. 23.
    Cantley LC, Neel BG (1999) New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci U S A 96(8):4240–4245PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Choi Y, Zhang J, Murga C, Yu H, Koller E, Monia BP, Gutkind JS, Li W (2002) PTEN, but not SHIP and SHIP2, suppresses the PI3K/Akt pathway and induces growth inhibition and apoptosis of myeloma cells. Oncogene 21(34):5289–5300PubMedCrossRefGoogle Scholar
  25. 25.
    Stambolic V, Suzuki A, de la Pompa JL, Brothers GM, Mirtsos C, Sasaki T, Ruland J, Penninger JM, Siderovski DP, Mak TW (1998) Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell 95(1):29–39PubMedCrossRefGoogle Scholar
  26. 26.
    Stiles B, Gilman V, Khanzenzon N, Lesche R, Li A, Qiao R, Liu X, Wu H (2002) Essential role of AKT-1/protein kinase B alpha in PTEN-controlled tumorigenesis. Mol Cell Biol 22(11):3842–3851PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Nakashima N, Sharma PM, Imamura T, Bookstein R, Olefsky JM (2000) The tumor suppressor PTEN negatively regulates insulin signaling in 3T3-L1 adipocytes. J Biol Chem 275(17):12889–12895PubMedCrossRefGoogle Scholar
  28. 28.
    Shan X, Czar MJ, Bunnell SC, Liu P, Liu Y, Schwartzberg PL, Wange RL (2000) Deficiency of PTEN in Jurkat T cells causes constitutive localization of Itk to the plasma membrane and hyperresponsiveness to CD3 stimulation. Mol Cell Biol 20(18):6945–6957PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Horie Y, Suzuki A, Kataoka E, Sasaki T, Hamada K, Sasaki J, Mizuno K, Hasegawa G, Kishimoto H, Iizuka M, Naito M, Enomoto K, Watanabe S, Mak TW, Nakano T (2004) Hepatocyte-specific PTEN deficiency results in steatohepatitis and hepatocellular carcinomas. J Clin Invest 113(12):1774–1783PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Stiles B, Wang Y, Stahl A, Bassilian S, Lee WP, Kim YJ, Sherwin R, Devaskar S, Lesche R, Magnuson MA, Wu H (2004) Liver-specific deletion of negative regulator PTEN results in fatty liver and insulin hypersensitivity [corrected]. Proc Natl Acad Sci U S A 101(7):2082–2087PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Watanabe S, Horie Y, Suzuki A (2005) Hepatocyte-specific PTEN-deficient mice as a novel model for nonalcoholic steatohepatitis and hepatocellular carcinoma. Hepatol Res 33(2):161–166PubMedCrossRefGoogle Scholar
  32. 32.
    Sato W, Horie Y, Kataoka E, Ohshima S, Dohmen T, Iizuka M, Sasaki J, Sasaki T, Hamada K, Kishimoto H, Suzuki A, Watanabe S (2006) Hepatic gene expression in hepatocyte-specific PTEN deficient mice showing steatohepatitis without ethanol challenge. Hepatol Res 34(4):256–265PubMedCrossRefGoogle Scholar
  33. 33.
    He L, Hou X, Kanel G, Zeng N, Galicia V, Wang Y, Yang J, Wu H, Birnbaum MJ, Stiles BL (2010) The critical role of AKT2 in hepatic steatosis induced by PTEN loss. Am J Pathol 176(5):2302–2308PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Onishi Y, Honda M, Ogihara T, Sakoda H, Anai M, Fujishiro M, Ono H, Shojima N, Fukushima Y, Inukai K, Katagiri H, Kikuchi M, Oka Y, Asano T (2003) Ethanol feeding induces insulin resistance with enhanced PI 3-kinase activation. Biochem Biophys Res Commun 303(3):788–794PubMedCrossRefGoogle Scholar
  35. 35.
    Yeon JE, Califano S, Xu J, Wands JR, De La Monte SM (2003) Potential role of PTEN phosphatase in ethanol-impaired survival signaling in the liver. Hepatology 38(3):703–714PubMedCrossRefGoogle Scholar
  36. 36.
    Derdak Z, Lang CH, Villegas KA, Tong M, Mark NM, de la Monte SM, Wands JR (2011) Activation of p53 enhances apoptosis and insulin resistance in a rat model of alcoholic liver disease. J Hepatol 54(1):164–172PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Taniguchi CM, Tran TT, Kondo T, Luo J, Ueki K, Cantley LC, Kahn CR (2006) Phosphoinositide 3-kinase regulatory subunit p85alpha suppresses insulin action via positive regulation of PTEN. Proc Natl Acad Sci U S A 103(32):12093–12097PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Lieber CS, Leo MA, Wang X, Decarli LM (2008) Alcohol alters hepatic FoxO1, p53, and mitochondrial SIRT5 deacetylation function. Biochem Biophys Res Commun 373(2):246–252PubMedCrossRefGoogle Scholar
  39. 39.
    He L, Marecki JC, Serrero G, Simmen FA, Ronis MJ, Badger TM (2007) Dose-dependent effects of alcohol on insulin signaling: partial explanation for biphasic alcohol impact on human health. Mol Endocrinol 21(10):2541–2550PubMedCrossRefGoogle Scholar
  40. 40.
    He L, Simmen FA, Mehendale HM, Ronis MJ, Badger TM (2006) Chronic ethanol intake impairs insulin signaling in rats by disrupting Akt association with the cell membrane. Role of TRB3 in inhibition of Akt/protein kinase B activation. J Biol Chem 281(16):11126–11134PubMedCrossRefGoogle Scholar
  41. 41.
    Du K, Herzig S, Kulkarni RN, Montminy M (2003) TRB3: a tribbles homolog that inhibits Akt/PKB activation by insulin in liver. Science 300(5625):1574–1577PubMedCrossRefGoogle Scholar
  42. 42.
    Shearn CT, Smathers RL, Backos DS, Reigan P, Orlicky DJ, Petersen DR (2013) Increased carbonylation of the lipid phosphatase PTEN contributes to Akt2 activation in a murine model of early alcohol-induced steatosis. Free Radic Biol Med 65C:680–692CrossRefGoogle Scholar
  43. 43.
    Vinciguerra M, Veyrat-Durebex C, Moukil MA, Rubbia-Brandt L, Rohner-Jeanrenaud F, Foti M (2008) PTEN down-regulation by unsaturated fatty acids triggers hepatic steatosis via an NF-kappaBp65/mTOR-dependent mechanism. Gastroenterology 134(1):268–280PubMedCrossRefGoogle Scholar
  44. 44.
    Alisi A, Bruscalupi G, Pastore A, Petrini S, Panera N, Massimi M, Tozzi G, Leoni S, Piemonte F, Nobili V (2011) Redox homeostasis and posttranslational modifications/activity of phosphatase and tensin homolog in hepatocytes from rats with diet-induced hepatosteatosis. J Nutr Biochem 23(2):169–178PubMedCrossRefGoogle Scholar
  45. 45.
    Kwon J, Lee SR, Yang KS, Ahn Y, Kim YJ, Stadtman ER, Rhee SG (2004) Reversible oxidation and inactivation of the tumor suppressor PTEN in cells stimulated with peptide growth factors. Proc Natl Acad Sci U S A 101(47):16419–16424PubMedCentralPubMedCrossRefGoogle Scholar
  46. 46.
    Lee SR, Yang KS, Kwon J, Lee C, Jeong W, Rhee SG (2002) Reversible inactivation of the tumor suppressor PTEN by H2O2. J Biol Chem 277(23):20336–20342PubMedCrossRefGoogle Scholar
  47. 47.
    Shi Y, Paluch BE, Wang X, Jiang X (2012) PTEN at a glance. J Cell Sci 125(Pt 20):4687–4692PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Song MS, Salmena L, Pandolfi PP (2012) The functions and regulation of the PTEN tumour suppressor. Nat Rev Mol Cell Biol 13(5):283–296PubMedGoogle Scholar
  49. 49.
    Yu CX, Li S, Whorton AR (2005) Redox regulation of PTEN by S-nitrosothiols. Mol Pharmacol 68(3):847–854PubMedGoogle Scholar
  50. 50.
    Xiao Y, Yeong Chit Chia J, Gajewski JE, Sio Seng Lio D, Mulhern TD, Zhu HJ, Nandurkar H, Cheng HC (2007) PTEN catalysis of phospholipid dephosphorylation reaction follows a two-step mechanism in which the conserved aspartate-92 does not function as the general acid–mechanistic analysis of a familial Cowden disease-associated PTEN mutation. Cell Signal 19(7):1434–1445PubMedCrossRefGoogle Scholar
  51. 51.
    Cao J, Schulte J, Knight A, Leslie NR, Zagozdzon A, Bronson R, Manevich Y, Beeson C, Neumann CA (2009) Prdx1 inhibits tumorigenesis via regulating PTEN/AKT activity. EMBO J 28(10):1505–1517PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    Hui ST, Andres AM, Miller AK, Spann NJ, Potter DW, Post NM, Chen AZ, Sachithanantham S, Jung DY, Kim JK, Davis RA (2008) Txnip balances metabolic and growth signaling via PTEN disulfide reduction. Proc Natl Acad Sci U S A 105(10):3921–3926PubMedCentralPubMedCrossRefGoogle Scholar
  53. 53.
    Covey TM, Edes K, Coombs GS, Virshup DM, Fitzpatrick FA (2010) Alkylation of the tumor suppressor PTEN activates Akt and beta-catenin signaling: a mechanism linking inflammation and oxidative stress with cancer. PLoS One 5(10):e13545PubMedCentralPubMedCrossRefGoogle Scholar
  54. 54.
    Esterbauer H, Schaur RJ, Zollner H (1991) Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Radic Biol Med 11(1):81–128PubMedCrossRefGoogle Scholar
  55. 55.
    Schaur RJ (2003) Basic aspects of the biochemical reactivity of 4-hydroxynonenal. Mol Aspects Med 24(4–5):149–159PubMedCrossRefGoogle Scholar
  56. 56.
    Smathers RL, Galligan JJ, Stewart BJ, Petersen DR (2011) Overview of lipid peroxidation products and hepatic protein modification in alcoholic liver disease. Chem Biol Interact 192(1–2):107–112PubMedCentralPubMedCrossRefGoogle Scholar
  57. 57.
    Shearn CT, Fritz KS, Reigan P, Petersen DR (2011) Modification of Akt2 by 4-hydroxynonenal inhibits insulin-dependent Akt signaling in HepG2 cells. Biochemistry 50(19):3984–3996PubMedCrossRefGoogle Scholar
  58. 58.
    Shearn CT, Smathers RL, Stewart BJ, Fritz KS, Galligan JJ, Hail N Jr, Petersen DR (2011) Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) inhibition by 4-hydroxynonenal leads to increased Akt activation in hepatocytes. Mol Pharmacol 79(6):941–952PubMedCentralPubMedCrossRefGoogle Scholar
  59. 59.
    Carver DJ, Gaston B, Deronde K, Palmer LA (2007) Akt-mediated activation of HIF-1 in pulmonary vascular endothelial cells by S-nitrosoglutathione. Am J Respir Cell Mol Biol 37(3):255–263PubMedCentralPubMedCrossRefGoogle Scholar
  60. 60.
    Galligan JJ, Smathers RL, Shearn CT, Fritz KS, Backos DS, Jiang H, Franklin CC, Orlicky DJ, Maclean KN, Petersen DR (2012) Oxidative stress and the ER stress response in a murine model for early-stage alcoholic liver disease. J Toxicol 2012:207594PubMedCentralPubMedCrossRefGoogle Scholar
  61. 61.
    Okumura K, Mendoza M, Bachoo RM, DePinho RA, Cavenee WK, Furnari FB (2006) PCAF modulates PTEN activity. J Biol Chem 281(36):26562–26568PubMedCrossRefGoogle Scholar
  62. 62.
    Ikenoue T, Inoki K, Zhao B, Guan KL (2008) PTEN acetylation modulates its interaction with PDZ domain. Cancer Res 68(17):6908–6912PubMedCrossRefGoogle Scholar
  63. 63.
    Fritz KS, Galligan JJ, Hirschey MD, Verdin E, Petersen DR (2012) Mitochondrial acetylome analysis in a mouse model of alcohol-induced liver injury utilizing SIRT3 knockout mice. J Proteome Res 11(3):1633–1643PubMedCentralPubMedCrossRefGoogle Scholar
  64. 64.
    Hirschey MD, Shimazu T, Jing E, Grueter CA, Collins AM, Aouizerat B, Stancakova A, Goetzman E, Lam MM, Schwer B, Stevens RD, Muehlbauer MJ, Kakar S, Bass NM, Kuusisto J, Laakso M, Alt FW, Newgard CB, Farese RV Jr, Kahn CR, Verdin E (2011) SIRT3 deficiency and mitochondrial protein hyperacetylation accelerate the development of the metabolic syndrome. Mol Cell 44(2):177–190PubMedCentralPubMedCrossRefGoogle Scholar
  65. 65.
    Lan F, Cacicedo JM, Ruderman N, Ido Y (2008) SIRT1 modulation of the acetylation status, cytosolic localization, and activity of LKB1. Possible role in AMP-activated protein kinase activation. J Biol Chem 283(41):27628–27635PubMedCentralPubMedCrossRefGoogle Scholar
  66. 66.
    Yao XH, Nyomba BL (2008) Hepatic insulin resistance induced by prenatal alcohol exposure is associated with reduced PTEN and TRB3 acetylation in adult rat offspring. Am J Physiol Regul Integr Comp Physiol 294(6):R1797–R1806PubMedCrossRefGoogle Scholar
  67. 67.
    Shen Z, Liang X, Rogers CQ, Rideout D, You M (2010) Involvement of adiponectin-SIRT1-AMPK signaling in the protective action of rosiglitazone against alcoholic fatty liver in mice. Am J Physiol Gastrointest Liver Physiol 298(3):G364–374PubMedCentralPubMedCrossRefGoogle Scholar
  68. 68.
    Chang CJ, Mulholland DJ, Valamehr B, Mosessian S, Sellers WR, Wu H (2008) PTEN nuclear localization is regulated by oxidative stress and mediates p53-dependent tumor suppression. Mol Cell Biol 28(10):3281–3289PubMedCentralPubMedCrossRefGoogle Scholar
  69. 69.
    Vazquez F, Grossman SR, Takahashi Y, Rokas MV, Nakamura N, Sellers WR (2001) Phosphorylation of the PTEN tail acts as an inhibitory switch by preventing its recruitment into a protein complex. J Biol Chem 276(52):48627–48630PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Department of Pharmaceutical SciencesUniversity of Colorado Denver Anchutz Medical CampusAuroraUSA

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