Lipid peroxidation and cell cycle signaling : 4-hydroxynonenal, a key molecule in stress mediated signaling.
Languages of publication
Role of lipid peroxidation products, particularly 4-hydroxynonenal (4-HNE) in cell cycle signaling is becoming increasingly clear. In this article, recent studies suggesting an important role of 4-HNE in stress mediated signaling for apoptosis are critically evaluated. Evidence demonstrating the modulation of UV, oxidative stress, and chemical stress mediated apoptosis by blocking lipid peroxidation by the α-class glutathione S-transferases (GSTs) is presented which suggest an important role of these enzymes in protection against oxidative stress and a role of lipid peroxidation products in stress mediated signaling. Overexpression of 4-HNE metabolizing GSTs (mGSTA4-4, hGSTA4-4, or hGST5.8) protects cells against 4-HNE, oxidative stress (H2O2 or xanthine/xanthine oxidase), and UV-A mediated apoptosis by blocking JNK and caspase activation suggesting a role of 4-HNE in the mechanisms of apoptosis caused by these stress factors. The intracellular concentration of 4-HNE appears to be crucial for the nature of cell cycle signaling and may be a determinant for the signaling for differentiation, proliferation, transformation, or apoptosis. The intracellular concentrations of 4-HNE are regulated through a coordinated action of GSTs (GSTA4-4 and hGST5.8) which conjugate 4-HNE to GSH to form the conjugate (GS-HNE) and the transporter 76 kDa Ral-binding GTPase activating protein (RLIP76), which catalyze ATP-dependent transport of GS-HNE. A mild stress caused by heat, UV-A, or H2O2 with no apparent effect on the cells in culture causes a rapid, transient induction of hGST5.8 and RLIP76. These stress preconditioned cells acquire ability to metabolize and exclude 4-HNE at an accelerated pace and acquire relative resistance to apoptosis by UV and oxidative stress as compared to unconditioned control cells. This resistance of stress preconditioned cells can be abrogated by coating the cells with anti-RLIP76 antibodies which block the transport of GS-HNE. These studies and previous reports discussed in this article strongly suggest a key role of 4-HNE in stress mediated signaling.
- Acworth IN, McCabe DR, Maher TJ. (1997) The analysis of free radicals, their reaction products, and antioxidants. In Oxidants, Antioxidants, and Free Radicals. Baskin SI, Salem H, eds, pp 23-77. Taylor & Francis, Washington, DC.
- Alin P, Danielson UH, Mannervik B. (1985) 4-Hydroxyalk-2-enals are substrates for glutathione transferase. FEBS Lett.; 179: 267-70.
- Ames BN, Shigenaga MK, Hagen TM. (1993) Oxidants, antioxidants, and the degenerative diseases of aging. Proc Natl Acad Sci U S A.; 90: 7915-22.
- Awasthi YC, Beutler E, Srivastava SK. (1975) Purification and properties of human erythrocyte glutathione peroxidase. J Biol Chem.; 250: 5144-9.
- Awasthi YC, Dao DD, Saneto RP. (1980) Interrelationship between anionic and cationic forms of glutathione S-transferases of human liver. Biochem J.; 191: 1-10.
- Awasthi S, Singhal SS, Srivastava SK, Zimniak P, Bajpai KK, Saxena M, Sharma R, Ziller SA 3rd, Frenkel EP, Singh SV, He NG, Awasthi YC. (1994) Adenosine triphosphate-dependent transport of doxorubicin, daunomycin, and vinblastine in human tissues by a mechanism distinct from the P-glycoprotein. J Clin Invest.; 93: 958-65.
- Awasthi S, Singhal SS, Srivastava SK, Torman RT, Zimniak P, Bandorowicz-Pikula J, Singh SV, Piper JT, Awasthi YC, Pikula S. (1998a) ATP-Dependent human erythrocyte glutathione-conjugate transporter. I. Purification, photoaffinity labeling, and kinetic characteristics of ATPase activity. Biochemistry.; 37: 5231-8.
- Awasthi S, Singhal SS, Pikula S, Piper JT, Srivastava SK, Torman RT, Bandorowicz-Pikula J, Lin JT, Singh SV, Zimniak P, Awasthi YC. (1998b) ATP-Dependent human erythrocyte glutathione-conjugate transporter. II. Functional reconstitution of transport activity. Biochemistry.; 37: 5239-48.
- Awasthi S, Cheng JZ, Singhal SS, Saini MK, Pandya U, Pikula S, Bandorowicz-Pikula J, Singh SV, Zimniak P, Awasthi YC. (2000) Novel function of human RLIP76: ATP-dependent transport of glutathione conjugates and doxorubicin. Biochemistry.; 39: 9327-34.
- Awasthi S, Cheng JZ, Singhal SS, Pandya U, Sharma R, Singh SV, Zimniak P, Awasthi YC. (2001) Functional reassembly of ATP-dependent xenobiotic transport by the N- and C-terminal domains of RLIP76 and identification of ATP binding sequences. Biochemistry.; 40: 4159-68.
- Awasthi S, Sharma R, Singhal SS, Zimniak P, Awasthi YC. (2002) RLIP76, a novel transporter catalyzing ATP-dependent efflux of xenobiotics. Drug Metab Dispos.; 30: 1300-10.
- Awasthi S, Singhal SS, Singhal J, Cheng J, Zimniak P, Awasthi YC. (2003a) Role of RLIP76 in lung cancer doxorubicin resistance: II. Doxorubicin transport in lung cancer by RLIP76. Int J Oncol.; 22: 713-20.
- Awasthi S, Singhal SS, Singhal J, Yang Y, Zimniak P, Awasthi YC. (2003b) Role of RLIP76 in lung cancer doxorubicin resistance: III. Anti-RLIP76 antibodies trigger apoptosis in lung cancer cells and synergistically increase doxorubicin cytotoxicity. Int J Oncol.; 22: 721-32.
- Barrera G, Pizzimenti S, Serra A, Ferretti C, Fazio VM, Saglio G, Dianzani MU. (1996) 4-Hydroxynonenal specifically inhibits c-myb but does not affect c-fos expressions in HL-60 cells. Biochem Biophys Res Commun.; 227: 589-93.
- Beckman JS, Koppenol WH. (1996) Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. Am J Physiol.; 271: C1424-37.
- Bhuyan KC, Bhuyan DK, Podos SM. (1986) Lipid peroxidation in cataract of the human. Life Sci.; 38: 1463-71.
- Brigelius-Flohe R, Friedrichs B, Maurer S, Schultz M, Streicher R. (1997) Interleukin-1-induced nuclear factor kappa B activation is inhibited by overexpression of phospholipid hydroperoxide glutathione peroxidase in a human endothelial cell line. Biochem J.; 328: 199-203.
- Camandola S, Poli G, Mattson MP. (2000) The lipid peroxidation product 4-hydroxy-2,3-nonenal increases AP-1-binding activity through caspase activation in neurons. J Neurochem.; 74: 159-68.
- Chen Q, Ames BN. (1994) Senescence-like growth arrest induced by hydrogen peroxide in human diploid fibroblast F65 cells. Proc Natl Acad Sci U S A.; 91: 4130-4.
- Cheng JZ, Singhal SS, Saini M, Singhal J, Piper JT, Van Kuijk FJ, Zimniak P, Awasthi YC, Awasthi S. (1999) Effects of mGST A4 transfection on 4-hydroxynonenal-mediated apoptosis and differentiation of K562 human erythroleukemia cells. Arch Biochem Biophys.; 372: 29-36.
- Cheng JZ, Sharma R, Yang Y, Singhal SS, Sharma A, Saini MK, Singh SV, Zimniak P, Awasthi S, Awasthi YC. (2001a) Accelerated metabolism and exclusion of 4-hydroxynonenal through induction of RLIP76 and hGST5.8 is an early adaptive response of cells to heat and oxidative stress. J Biol Chem.; 276: 41213-23.
- Cheng JZ, Singhal SS, Sharma A, Saini M, Yang Y, Awasthi S, Zimniak P, Awasthi YC. (2001b) Transfection of mGSTA4 in HL-60 cells protects against 4-hydroxynonenal-induced apoptosis by inhibiting JNK-mediated signaling. Arch Biochem Biophys.; 392: 197-207.
- Cheng JZ, Yang Y, Singh SP, Singhal SS, Awasthi S, Pan SS, Singh SV, Zimniak P, Awasthi YC. (2001c) Two distinct 4-hydroxynonenal metabolizing glutathione S-transferase isozymes are differentially expressed in human tissues. Biochem Biophys Res Commun.; 282: 1268-74.
- Chu FF, Doroshow JH, Esworthy RS. (1993) Expression, characterization, and tissue distribution of a new cellular selenium-dependent glutathione peroxidase, GSHPx-GI. J Biol Chem.; 268: 2571-6.
- Craven PA, Pfanstiel J, DeRubertis FR. (1986) Role of reactive oxygen in bile salt stimulation of colonic epithelial proliferation. J Clin Invest.; 77: 850-9.
- Crawford DR, Schools GP, Davies KJ. (1996) Oxidant-inducible adapt15 RNA is associated with growth arrest- and DNA damage-inducible gadd153 and gadd45. Arch Biochem Biophys.; 329: 137-44.
- Davies KJ. (2000) Oxidative stress, antioxidant defenses, and damage removal, repair, and replacement systems. IUBMB Life.; 50: 279-89.
- Dianzani MU, Barrera G, Parola M. (1999) 4-Hydroxy-2,3-nonenal as a signal for cell function and differentiation. Acta Biochim Polon.; 46: 61-75.
- Esterbauer H, Schaur RJ, Zollner H. (1991) Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Radic Biol Med.; 11: 81-128.
- Foley TD. (2001) The cyclooxygenase hydroperoxide product PGG2 activates synaptic nitric oxide synthase: a possible antioxidant response to membrane lipid peroxidation. Biochem Biophys Res Commun.; 286: 235-8.
- Guo YL, Kang B, Williamson JR. (1998) Inhibition of the expression of mitogen-activated protein phosphatase-1 potentiates apoptosis induced by tumor necrosis factor-alpha in rat mesangial cells. J Biol Chem.; 273: 10362-6.
- Hartley DP, Ruth JA, Petersen DR. (1995) The hepatocellular metabolism of 4-hydroxynonenal by alcohol dehydrogenase, aldehyde dehydrogenase, and glutathione S-transferase. Arch Biochem Biophys.; 316: 197-205.
- Hayes JD, Pulford DJ. (1995) The glutathione S-transferase supergene family: regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance. Crit Rev Biochem Mol Biol.; 30: 445-600.
- Heery JM, Kozak M, Stafforini DM, Jones DA, Zimmerman GA, McIntyre TM, Prescott SM. (1995) Oxidatively modified LDL contains phospholipids with platelet-activating factor-like activity and stimulates the growth of smooth muscle cells. J Clin Invest.; 96: 2322-30.
- Hiratsuka A, Yamane H, Yamazaki S, Ozawa N, Watabe T. (1997) Subunit Ya-specific glutathione peroxidase activity toward cholesterol 7-hydroperoxides of glutathione S-transferases in cytosols from rat liver and skin. J Biol Chem.; 272: 4763-9.
- Hubatsch I, Ridderstrom M, Mannervik B. (1998) Human glutathione S-transferase A4-4: an alpha class enzyme with high specificity for 4-hydroxynoneal and other genototoxic products of lipid peroxidation. Biochem J.; 330: 175-9.
- Ikebuchi Y, Masumoto N, Tasaka K, Koike K, Kasahara K, Miyake A, Tanizawa O. (1991) Superoxide anion increases intracellular pH, intracellular free calcium, and arachidonate release in human amnion cells. J Biol Chem.; 266: 13233-7.
- Ishikawa T. (1992) The ATP-dependent glutathione S-conjugate export pump. Trends Biochem Sci.; 17: 463-8.
- Jullien-Flores V, Dorseuil O, Romero F, Letourneur F, Saragosti S, Berger R, Tavitian A, Gacon G, Camonis JH. (1995) Bridging Ral GTPase to Rho pathways. RLIP76, a Ral effector with CDC42/Rac GTPase-activating protein activity. J Biol Chem.; 270: 22473-7.
- Kruman I, Bruce-Keller AJ, Bredesen D, Waeg G, Mattson MP. (1997) Evidence that 4-hydroxynonenal mediates oxidative stress-induced neuronal apoptosis. J Neurosci.; 17: 5089-100.
- Lawrence RA, Burk RF. (1976) Glutathione peroxidase activity in selenium-deficient rat liver. Biochem Biophys Res Commun.; 71: 952-8.
- Leonarduzzi G, Arkan MC, Basaga H, Chiarpotto E, Sevanian A, Poli G. (2000) Lipid oxidation products in cell signaling. Free Radic Biol Med.; 28: 1370-8.
- Mannervik B, Danielson UH. (1988) Glutathione transferases - structure and catalytic activity. CRC Crit Rev Biochem.; 23: 283-337.
- Mannervik B, Awasthi YC, Board PG, Hayes JD, Di Ilio C, Ketterer B, Listowsky I, Morgenstern R, Muramatsu M, Pearson WR, Pickett, CB, Sato K, Widersten M, Wolf CR. (1992) Nomenclature for human glutathione transferases. Biochem J.; 282: 305-6.
- Markesbery WR, Lovell MA. (1997) Four-hydroxynonenal, a product of lipid peroxidation, is increased in the brain in Alzheimer's disease. Neurobiol Aging.; 19: 33-6.
- Medh RD, Saxena M, Singhal SS, Ahmad H, Awasthi YC. (1991) Characterization of a novel glutathione S-transferase isoenzyme from mouse lung and liver having structural similarity to rat glutathione S-transferase 8-8. Biochem J.; 278: 793-9.
- Murrell GA, Francis MJ, Bromley L. (1990) Modulation of fibroblast proliferation by oxygen free radicals. Biochem J.; 265: 659-65.
- Parola M, Robino G, Marra F, Pinzani M, Bellomo G, Leonarduzzi G, Chiarugi P, Camandola S, Poli G, Waeg G, Gentilini P, Dianzani MU. (1998) HNE interacts directly with JNK isoforms in human hepatic stellate cells. J Clin Invest.; 102: 1942-50.
- Poli G, Schaur RJ. (2000) 4-Hydroxynonenal in the pathomechanisms of oxidative stress. IUBMB Life.; 50: 315-21.
- Prohaska JR, Ganther HE. (1976) Glutathione peroxidase activity of glutathione-S-transferases purified from rat liver. Biochem Biophys Res Commun.; 76: 437-45.
- Pulaski L, Jedlitschky G, Leier I, Buchholz U, Keppler D. (1996) Identification of the multidrug-resistance protein (MRP) as the glutathione-S-conjugate export pump of erythrocytes. Eur J Biochem.; 241: 644-8.
- Rashba-Step J, Tatoyan A, Duncan R, Ann D, Pushpa-Rehka TR, Sevanian A. (1997) Phospholipid peroxidation induces cytosolic phospholipase A2 activity: membrane effects versus enzyme phosphorylation. Arch Biochem Biophys.; 343: 44-54.
- Renes J, de Vries EE, Hooiveld GJ, Krikken I, Jansen PL, Muller M. (2000) Multidrug resistance protein MRP1 protects against the toxicity of the major lipid peroxidation product 4-hydroxynonenal. Biochem J.; 350: 555-61.
- Ruef J, Rao GN, Li F, Bode C, Patterson C, Bhatnagar A, Runge MS. (1998) Induction of rat aortic smooth muscle cell growth by the lipid peroxidation product 4-hydroxy-2-nonenal. Circulation.; 97: 1071-8.
- Schnurr K, Belkner J, Ursini F, Schewe T, Kuhn H. (1996) The selenoenzyme phospholipid hydroperoxide glutathione peroxidase controls the activity of the 15-lipoxygenase with complex substrates and preserves the specificity of the oxygenation products. J Biol Chem.; 271: 4653-8.
- Seger R, Krebs EG. (1995). The MAPK signaling cascade. FASEB J.; 9: 726-35.
- Sharma R., Singhal SS, Cheng JZ, Yang Y, Sharma A, Zimniak P, Awasthi S, Awasthi YC. (2001) RLIP76 is the major ATP-dependent transporter of glutathione-conjugates and doxorubicin in human erythrocytes. Arch Biochem Biophys.; 391: 171-9.
- Sharma R, Sharma A, Yang Y, Awasthi S, Singhal SS, Zimniak P, Awasthi YC. (2002) Functional reconstitution of Ral-binding GTPase activating protein, RLIP76, in proteoliposomes catalyzing ATP-dependent transport of glutathione conjugate of 4-hydroxynonenal. Acta Biochim Polon.; 49: 693-701.
- Sies H. (1985) Oxidative stress: introductory remarks. In Oxidative Stress. Sies H, ed, pp 1-8. Academic Press, London.
- Singhal SS, Saxena M, Ahmad H, Awasthi S, Haque AK, Awasthi YC. (1992) Glutathione S-transferases of human lung: characterization and evaluation of the protective role of the alpha-class isozymes against lipid peroxidation. Arch Biochem Biophys.; 299: 232-41.
- Singhal SS, Zimniak P, Sharma R, Srivastava SK, Awasthi S, Awasthi YC. (1994a) A novel glutathione S-transferase isozyme similar to GST 8-8 of rat and mGSTA4-4 (GST 5.7) of mouse is selectively expressed in human tissues. Biochim Biophys Acta.; 1204: 279-86.
- Singhal SS, Zimniak P, Awasthi S, Piper JT, He NG, Teng JI, Petersen DR, Awasthi YC. (1994b) Several closely related glutathione S-transferase isozymes catalyzing conjugation of 4-hydroxynonenal are differentially expressed in human tissues. Arch Biochem Biophys.; 311: 242-50.
- Singhal SS, Awasthi S, Srivastava SK, Zimniak P, Ansari NH, Awasthi YC. (1995) Novel human ocular glutathione S-transferases with high activity toward 4-hydroxynonenal. Invest Ophthalmol Vis Sci.; 36: 142-50.
- Singhal SS, Godley BF, Chandra A, Pandya U, Jin GF, Saini MK, Awasthi S, Awasthi YC. (1999) Induction of glutathione S-transferase hGST 5.8 is an early response to oxidative stress in RPE cells. Invest Ophthalmol Vis Sci.; 40: 2652-9.
- Singhal SS, Singhal J, Sharma R, Singh SV, Zimniak P, Awasthi YC, Awasthi S. (2003) Role of RLIP76 in lung cancer doxorubicin resistance: I. The ATPase activity of RLIP76 correlates with doxorubicin and 4-hydroxynonenal resistance in lung cancer cells. Int J Oncol.; 22: 365-75.
- Soh Y, Jeong KS, Lee IJ, Bae MA, Kim YC, Song BJ. (2000) Selective activation of the c-Jun N-terminal protein kinase pathway during 4-hydroxynonenal-induced apoptosis of PC12 cells. Mol Pharmacol.; 58: 535-41.
- Srivastava S, Chandra A, Bhatnagar A, Srivastava SK, Ansari NH. (1995) Lipid peroxidation product, 4-hydroxynonenal and its conjugate with GSH are excellent substrates of bovine lens aldose reductase. Biochem Biophys Res Commun.; 217: 741-6.
- Srivastava S, Chandra A, Wang LF, Seifert WE Jr, DaGue BB, Ansari NH, Srivastava SK, Bhatnagar A. (1998) Metabolism of the lipid peroxidation product, 4-hydroxy-trans-2-nonenal, in isolated perfused rat heart. J Biol Chem.; 273: 10893-900.
- Stenberg G, Ridderstrom M, Engstrom A, Pemble SE, Mannervik B. (1992) Cloning and heterologous expression of cDNA encoding class alpha rat glutathione transferase 8-8, an enzyme with high catalytic activity towards genotoxic a,b-unsaturated carbonyl compounds. Biochem J.; 284: 313-9.
- Suzuki YJ, Forman HJ, Sevanian A. (1997) Oxidants as stimulators of signal transduction. Free Radic Biol Med.; 22: 269-85.
- Takahashi K, Avissar N, Whitin J, Cohen H. (1987) Purification and characterization of human plasma glutathione peroxidase: a selenoglycoprotein distinct from the known cellular enzyme. Arch Biochem Biophys.; 256: 677-86.
- Tan KH, Meyer DJ, Belin J, Ketterer B. (1984) Inhibition of microsomal lipid peroxidation by glutathione and glutathione transferases B and AA. Role of endogenous phospholipase A2. Biochem J.; 220: 243-52.
- Thomas JP, Maiorino M, Ursini F, Girotti AW. (1990) Protective action of phospholipid hydroperoxide glutathione peroxidase against membrane-damaging lipid peroxidation. In situ reduction of phospholipid and cholesterol hydroperoxides. J Biol Chem.; 265: 454-61.
- Uchida K, Shiraishi M, Naito Y, Torii Y, Nakamura Y, Osawa T. (1999) Activation of stress signaling pathways by the end product of lipid peroxidation. 4-Hydroxy-2-nonenal is a potential inducer of intracellular peroxide production. J Biol Chem.; 274: 2234-42.
- Ursini F, Maiorino M, Gregolin C. (1985) The selenoenzyme phospholipid hydroperoxide glutathione peroxidase. Biochim Biophys Acta.; 839: 62-70.
- Witztum JL. (1994) The oxidation hypothesis of atherosclerosis. Lancet.; 344: 793-5.
- Yang Y, Cheng JZ, Singhal SS, Saini M, Pandya U, Awasthi S, Awasthi YC. (2001) Role of glutathione S-transferases in protection against lipid peroxidation. Overexpression of hGSTA2-2 in K562 cells protects against hydrogen peroxide-induced apoptosis and inhibits JNK and caspase 3 activation. J Biol Chem.; 276: 19220-30.
- Yang Y, Sharma R, Cheng JZ, Saini MK, Ansari NH, Andley UP, Awasthi S, Awasthi YC. (2002a). Transfection of HLE B-3 cells with hGSTA1 or hGSTA2 protects against hydrogen peroxide and naphthalene induced lipid peroxidation and apoptosis. Invest Ophthalmol Vis Sci.; 43: 434-45.
- Yang Y, Sharma R, Zimniak P, Awasthi YC. (2002b) Role of alpha class glutathione S-transferases as antioxidant enzymes in rodent tissues. Toxicol Appl Pharmacol.; 182: 105-15.
- Yoritaka A, Hattori N, Uchida K, Tanaka M, Stadtman ER, Mizuno Y. (1996) Immunohistochemical detection of 4-hydroxynonenal protein adducts in Parkinson disease. Proc Natl Acad Sci U S A.; 93: 2696-701.
- Zhao T, Singhal SS, Piper JT, Cheng JZ, Pandya U, Clark-Wronski J, Awasthi S, Awasthi YC. (1999) The role of human glutathione S-transferases hGSTA1-1 and hGSTA2-2 in protection against oxidative stress. Arch Biochem Biophys.; 367: 216-24.
- Zimniak P, Eckles MA, Saxena M, Awasthi YC. (1992) A subgroup of class alpha glutathione S-transferases.Cloning of cDNA for mouse lung glutathione S-transferase GST 5.7. FEBS Lett.; 313: 173-6.
- Zimniak P, Singhal SS, Srivastava SK, Awasthi S, Sharma R, Hayden JB, Awasthi YC. (1994) Estimation of genomic complexity, heterologous expression, and enzymatic characterization of mouse glutathione S-transferase mGSTA4-4 (GST 5.7). J Biol Chem.; 269: 992-1000.
Publication order reference