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Horm Metab Res 2011; 43(7): 445-451
DOI: 10.1055/s-0031-1277182
Original Basic

© Georg Thieme Verlag KG Stuttgart · New York

Alpha-Lipoic Acid Inhibits Endoplasmic Reticulum Stress-induced Cell Death Through PI3K/Akt Signaling Pathway in FRTL5 Thyroid Cells

S. J. Lee1 , S. H. Kim1 , J. G. Kang1 , C. S. Kim1 , S.-H. Ihm1 , M. G. Choi1 , H. J. Yoo1
  • 1Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon, Republic of Korea
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Publication History

received 11.01.2011

accepted 12.04.2011

Publication Date:
17 May 2011 (online)

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Abstract

Alpha-lipoic acid (ALA) has been shown to modulate cell death via PI3K/Akt signal pathway in various cells. In the present study, the effects of ALA on cell death and PI3K/Akt signal pathway linked to cell death-related proteins during endoplasmic reticulum (ER) stress in FRTL5 thyroid cells were evaluated. In FRTL5 thyroid cells, cell viability increased by ALA pretreatment in tunicamycin (TN)-treated cells. When TN was treated, CCAAT/enhancer-binding protein-homologous protein (CHOP) and Bax protein levels were elevated while Bcl-2 protein levels were reduced. ALA diminished CHOP and Bax protein levels, and augmented Bcl-2 protein levels in TN-treated cells. After exposure to TN, phospho-Akt protein levels were repressed whereas total Akt protein levels were not changed. ALA increased phospho-Akt protein levels but not total Akt protein levels in both non-TN-treated and TN-treated cells. After LY294002 administration in non-TN-treated cells, cell viability was reduced, and CHOP and Bax protein levels were elevated, and Bcl-2 protein levels were reduced. The CHOP, Bcl-2 and Bax protein levels were not different after LY294002 administration in TN-treated cells. LY294002 and wortmannin decreased cell viability, and increased CHOP and Bax protein levels, and decreased Bcl-2 protein levels in ALA-pretreated and TN-treated cells. In conclusion, these results suggest that ER stress may induce cell death by modulating PI3K/Akt signal pathway linked to cell death-related proteins in FRTL5 thyroid cells. Moreover, these findings imply that ALA may ameliorate ER stress-induced cell death by activating PI3K/Akt signal pathway and attenuating changes of cell death-related proteins in FRTL5 thyroid cells.

Key words

alpha-lipoic acid - cell death - Akt - thyroid - endoplasmic reticulum

References

  • 1 Oyadomari S, Mori M. Roles of CHOP/GADD153 in endoplasmic reticulum stress.  Cell Death Differ. 2004;  11 381-389
    Google Scholar
  • 2 Rutkowski DT, Kaufman RJ. A trip to the ER: coping with stress.  Trends Cell Biol. 2004;  14 20-28
    Google Scholar
  • 3 Kaufman RJ. Orchestrating the unfolded protein response in health and disease.  J Clin Invest. 2002;  110 1389-1398
    Google Scholar
  • 4 Zinszner H, Kuroda M, Wang XZ, Batchvarova N, Lightfoot RT, Remotti H, Stevens JL, Ron D. CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum.  Genes Dev. 1998;  12 982-995
    Google Scholar
  • 5 Mccullough KD, Martindale JL, Klotz LO, Aw TY, Holbrook NJ. Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating bcl2 and perturbing the cellular redox state.  Mol Cell Biol. 2001;  21 1249-1259
    Google Scholar
  • 6 Alnemri ES. Mammalian cell death proteases: a family of highly conserved aspartate specific cysteine proteases.  J Cell Biochem. 1997;  64 33-42
    Google Scholar
  • 7 Wei MC, Zong WX, Cheng EH, Lindsten T, Panoutsakopoulou V, Ross AJ, Roth KA, MacGregor G, Thompson CB, Korsmeyer SJ. Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death.  Science. 2001;  292 727-730
    Google Scholar
  • 8 Chan Yu V SL. Proteins of the Bcl-2 family in apoptosis signalling: from mechanistic insights to therapeutic opportunities.  Clin Exp Pharmacol Physiol. 2004;  31 119-128
    Google Scholar
  • 9 Hockenbery DM, Oltvai ZV, Yin XM, Milliman CL, Korsmeyer SJ. Bcl-2 functions in an antioxidant pathway to prevent apoptosis.  Cell. 1993;  75 241-251
    Google Scholar
  • 10 Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream.  Cell. 2007;  129 1261-1274
    Google Scholar
  • 11 Hosoi T, Hyoda K, Okuma Y, Nomura Y, Ozawa K. Inhibitory effect of 4-(2-aminoethyl)-benzenesulfonyl fluoride, a serine protease inhibitor, on PI3K inhibitor-induced CHOP expression.  Eur J Pharmacol. 2007;  554 8-11
    Google Scholar
  • 12 Hyoda K, Hosoi T, Horie N, Okuma Y, Ozawa K, Nomura Y. PI3K-Akt inactivation induced CHOP expression in endoplasmic reticulum-stressed cells.  Biochem Biophys Res Commun. 2006;  340 286-290
    Google Scholar
  • 13 Paker L, Witt EH, Tritschler JH. Alpha lipoic acid as a biological antioxidant.  Free Radic Biol Med. 1995;  19 227-250
    Google Scholar
  • 14 Ziegler D, Nowak H, Kempler P, Vargha P, Low PA. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a meta-analysis.  Diabet Med. 2004;  21 114-121
    Google Scholar
  • 15 Cameron NE, Coteer MA, Horrobin DH, Tritschler HJ. Effects of alpha-lipoic acid on neurovascular function in diabetic rats: interaction with essential fatty acids.  Diabetologia. 1998;  41 390-399
    Google Scholar
  • 16 Marsh SA, Laursen PB, Pat BK, Gobe GC, Coombes JS. Bcl-2 in endothelial cells is increased by vitamin E and alpha-lipoic acid supplementation but not exercise training.  J Mol Cell Cardiol. 2005;  38 445-451
    Google Scholar
  • 17 Shi DY, Liu HL, Stern JS, Yu PZ, Liu SL. Alpha-lipoic acid induces apoptosis in hepatoma cells via the PTEN/Akt pathway.  FEBS Lett. 2008;  582 1667-1671
    Google Scholar
  • 18 Dozio E, Ruscica M, Passafaro L, Dogliotti G, Steffani L, Pagani A, Demartini G, Esposti D, Fraschini F, Magni P. The natural antioxidant alpha-lipoic acid induces p27Kip1-dependent cell cycle arrest and apoptosis in MCF-7 human breast cancer cells.  Eur J Pharmacol. 2010;  641 29-34
    Google Scholar
  • 19 Moungjaroen J, Nimmannit U, Callery PS, Wang L, Azad N, Lipipun V, Chanvorachote P, Rojanasakul Y. Reactive oxygen species mediate caspase activation and apoptosis induced by lipoic acid in human lung epithelial cancer cells through Bcl-2 down-regulation.  J Pharmacol Exp Ther. 2006;  319 1062-1069
    Google Scholar
  • 20 Bitar MS, Ayed AK, Abdel-Halim SM, Isenovic ER, Al-Mulla F. Inflammation and apoptosis in aortic tissues of aged type II diabetes: amelioration with α-lipoic acid through phosphatidylinositol 3-kinase/Akt-dependent mechanism.  Life Sci. 2010;  86 844-853
    Google Scholar
  • 21 Artwohl M, Muth K, Kosulin K, de Martin R, Hölzenbein T, Rainer G, Freudenthaler A, Huttary N, Schmetterer L, Waldhäusl WK, Baumgartner-Parzer SM. R-(+)-α-lipoic acid inhibits endothelial cell apoptosis and proliferation: involvement of Akt and retinoblastoma protein/E2F-1.  Am J Physiol Endocrinol Metab. 2007;  293 E681-E689
    Google Scholar
  • 22 Diesel B, Kulhanek-Heinze S, Holtje M, Brandt B, Holtje HD, Vollmar AM, Kiemer AK. Alpha-lipoic acid as a directly binding activator of the insulin receptor: protection from hepatocyte apoptosis.  Biochemistry. 2007;  46 2146-2155
    Google Scholar
  • 23 Bitar MS, Wahid S, Pilcher CW, Al-Saleh E, Al-Mulla F. Alpha-lipoic acid mitigates insulin resistance in Goto-Kakizaki rats.  Horm Metab Res. 2004;  36 542-549
    Google Scholar
  • 24 Simbula G, Columbano A, Ledda-Columbano GM, Sanna L, Deidda M, Diana A, Pibiri M. Increased reactive oxygen species generation and p53 activation in alpha-lipoic acid-induced apoptosis of hepatoma cells.  Apoptosis. 2007;  12 113-123
    Google Scholar
  • 25 Smith AR, Shenvi SV, Widlansky M, Suh JH, Hagen TM. Lipoic acid as a potential therapy for chronic diseases associated with oxidative stress.  Curr Med Chem. 2004;  11 1135-1146
    Google Scholar
  • 26 Healy SJM, Gorman AM, Mousavi-Shafaei P, Gupta S, Samali A. Targeting the endoplasmic reticulum-stress response as an anticancer strategy.  Eur J Pharmacol. 2009;  625 234-246
    Google Scholar
  • 27 Kim PS, Ding M, Menon S, Jung CG, Cheng JM, Miyamoto T, Li B, Furudate S, Agui T. A missense mutation G2320R in the thyroglobulin gene causes nongoitrous congenital primary hypothyroidism in the WIC-rdw rat.  Mol Endocrinol. 2000;  14 1944-1953
    Google Scholar
  • 28 Ullman E, Fan Y, Stawowczyk M, Chen H-M, Yue Z, Zong W-X. Autophagy promotes necrosis in apoptosis-deficient cells in response to ER stress.  Cell Death and Differ. 2008;  15 422-425
    Google Scholar
  • 29 Müller C, Dünschede F, Koch E, Vollmar AM, Kiemer AK. α-Lipoic acid preconditioning reduces ischemia-reperfusion injury of the rat liver via the PI3-kinase/Akt pathway.  Am J Physiol Gastrointest Liver Physiol. 2003;  285 G769-G778
    Google Scholar
  • 30 Ki SH, Kim SG. Phase II enzyme induction by α-lipoic acid through phosphatidylinositol 3-kinase-dependent C/EBPs activation.  Xenobiotica. 2008;  38 587-604
    Google Scholar
  • 31 Pessler-Cohen D, Pekala PH, Kovsan J, Bloch-Damti A, Rudich A, Bashan N. GLUT4 repression in response to oxidative stress is associated with reciprocal alterations in C/EBP alpha and delta isoforms in 3T3-L1 adipocytes.  Arch Physiol Biochem. 2006;  112 3-12
    Google Scholar
  • 32 Guyton KZ, Xu Q, Holbrook NJ. Induction of the mammalian stress response gene GADD153 by oxidative stress: role of AP-1 element.  Biochem J. 1996;  314 547-554
    Google Scholar
  • 33 Saito J, Kohn AD, Roth RA, Noguchi Y, Tatsumo I, Hirai A, Suzuki K, Kohn LD, Saji M, Ringel MD. Regulation of FRTL-5 thyroid cell growth by phosphatidylinositol (OH) 3 kinase-dependent Akt-mediated signaling.  Thyroid. 2001;  11 339-351
    Google Scholar
  • 34 Srinivasan S, Ohsugi M, Liu Z, Fatrai S, Bernal-Mizrachi E, Permutt MA. Endoplasmic reticulum stress-induced apoptosis is partly mediated by reduced insulin signaling through phosphatidylinositol 3-kinase/Akt and increased glycogen synthase kinase-3beta in mouse insulinoma cells.  Diabetes. 2005;  54 968-975
    Google Scholar
  • 35 Luo HR, Hattori H, Hossain MA, Hester L, Huang Y, Lee-Kwon W, Donowitz M, Nagata E, Snyder SH. Akt as a mediator of cell death.  Proc Natl Acad Sci USA. 2003;  100 11712-11717
    Google Scholar
  • 36 Bailly-Maitre B, Fondevila C, Kaldas F, Droin N, Luciano F, Ricci J-E, Croxton R, Krajewska M, Zapata JM, Kupiec-Weglinski JW, Farmer D, Reed JC. Cytoprotective gene bi-1 is required for intrinsic protection from endoplasmic reticulum stress and ischemia-reperfusion injury.  Proc Natl Acad Sci USA. 2006;  103 2809-2814
    Google Scholar
  • 37 Duenschede F, Erbes K, Riegler N, Ewald P, Kircher A, Westermann S, Schad A, Miesmer I, Albrecht-Schöck S, Gockel I, Kiemer AK, Junginger T. Protective effects of ischemic preconditioning and application of lipoic acid prior to 90 min of hepatic ischemia in a rat model.  World J Gastroenterol. 2007;  13 3692-3698
    Google Scholar
  • 38 Viglietto G, Amodio N, Malanga D, Scrima M, De Marco C. Contribution of PKB/AKT signaling to thyroid cancer.  Front Biosci. 2011;  16 1461-1487
    Google Scholar
  • 39 Shinohara M, Chung YJ, Saji M, Ringel MD. AKT in thyroid tumorigenesis and progression.  Endocrinology. 2007;  148 942-947
    Google Scholar
  • 40 Wang XZ, Ron D. Stress-induced phosphorylation and activation of the transcription factor CHOP (GADD153) by p38 MAP kinase.  Science. 1996;  272 1347-1349
    Google Scholar
  • 41 Pomérance M, Carapau D, Chantoux F, Mockey M, Corrèze C, Francon J, Blondeau J-P. CCAAT/enhancer-binding protein-homologous protein expression and transcriptional activity are regulated by 3′,5′-cyclic adenosine monophosphate in thyroid cells.  Mol Endocrinol. 2003;  17 2283-2294
    Google Scholar
  • 42 Zou CG, Cao XZ, Zhao YS, Gao SY, Li SD, Liu XY, Zhang Y, Zhang KQ. The molecular mechanism of endoplasmic reticulum stress-induced apoptosis in PC-12 neuronal cells: the protective effect of insulin-like growth factor I.  Endocrinology. 2009;  150 277-285
    Google Scholar
  • 43 Lee SJ, Kim SH, Kang JG, Kim CS, Ihm SH, Choi MG, Yoo HJ. Effects of all-trans retinoic acid on sodium/iodide symporter and CCAAT/enhancer-binding protein-homologous protein under condition of endoplasmic reticulum stress in FRTL5 thyroid cells.  Horm Metab Res. 2011;  43 331-336
    Google Scholar
  • 44 Kim HJ, Kim JY, Lee SJ, Kim HJ, Oh CJ, Choi YK, Lee HJ, Do JY, Kim SY, Kwon TK, Choi HS, Lee MO, Park IS, Park KG, Lee KU, Lee IK. α-Lipoic acid prevents neointimal hyperplasia via induction of p38 mitogen-activated protein kinase/Nur77-mediated apoptosis of vascular smooth muscle cells and accelerates postinjury reendothelialization.  Arterioscler Thromb Vasc Biol. 2010;  30 2164-2172
    Google Scholar
  • 45 Lee SJ, Kang JG, Ryu OH, Kim CS, Ihm SH, Choi MG, Yoo HJ, Kim DS, Kim TW. Effects of α-lipoic acid on TGFβ1-p38 MAPK-fibronectin pathway in diabetic nephropathy.  Metabolism. 2009;  58 616-623
    Google Scholar

Correspondence

Prof. S. J. LeeMD, PhD 

Division of Endocrinology and

Metabolism

Department of Internal

Medicine

College of Medicine

Hallym University

200-704 Chuncheon

Republic of Korea

Phone: +82/31/380 3700

Fax: +82/31/383 3768

Email: leesj@hallym.ac.kr

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