Abstract
Anticancer activity of proteasome inhibitors has been demonstrated in various cancer cell types. However, mechanisms by which they exert anticancer action were not fully understood. The present study was undertaken to examine the effect of the proteasome inhibitor MG-132 and the underlying mechanism in glioma cells. MG-132 caused alterations in mitochondrial membrane potential and apoptosis-inducing factor (AIF) nuclear translocation. MG-132 induced reduction in ERK and Akt activation. The transient transfection of constitutively active forms of MEK, an upstream of ERK, and Akt blocked the MG-132-induced cell death. Similarly to down-regulation of Akt, expression levels of mTOR were inhibited by MG-132. Addition of rapamycin, an inhibitor of mTOR, caused stimulation of the MG-132-induced cell death. There were no significant changes in levels of XIAP, survivin, and Bax. Overexpression of constitutively active forms of MEK and Akt blocked the MG-132-induced AIF nuclear translocation. These findings indicate that MG-132 induces AIF nuclear translocation through down-regulation of ERK and Akt/mTOR pathways. These data suggest that proteasome inhibitors may serve as potential therapeutic agents for malignant human gliomas.
Similar content being viewed by others
References
Stewart LA (2002) Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials. Lancet 359(9311):1011–1018
Ohgaki H, Kleihues P (2005) Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas. J Neuropathol Exp Neurol 64(6):479–489
Johnstone RW, Ruefli AA, Lowe SW (2002) Apoptosis: a link between cancer genetics and chemotherapy. Cell 108(2):153–164
Adams J, Palombella VJ, Sausville EA, Johnson J, Destree A, Lazarus DD, Maas J, Pien CS, Prakash S, Elliott PJ (1999) Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res 59(11):2615–2622
Baumeister W, Walz J, Zuhl F, Seemuller E (1998) The proteasome: paradigm of a self-compartmentalizing protease. Cell 92(3):367–380
Sterz J, von Metzler I, Hahne JC, Lamottke B, Rademacher J, Heider U, Terpos E, Sezer O (2008) The potential of proteasome inhibitors in cancer therapy. Expert Opin Investig Drugs 17(6):879–895
Spano JP, Bay JO, Blay JY, Rixe O (2005) Proteasome inhibition: a new approach for the treatment of malignancies. Bull Cancer 92(11):E61–E66, 945–952
Denizot F, Lang R (1986) Rapid colorimetric assay for cell growth and survival. Modifications to the tetrazolium dye procedure giving improved sensitivity and reliability. J Immunol Methods 89(2):271–277
Kroemer G, Dallaporta B, Resche-Rigon M (1998) The mitochondrial death/life regulator in apoptosis and necrosis. Annu Rev Physiol 60:619–642
Pastorino JG, Snyder JW, Serroni A, Hoek JB, Farber JL (1993) Cyclosporin and carnitine prevent the anoxic death of cultured hepatocytes by inhibiting the mitochondrial permeability transition. J Biol Chem 268(19):13791–13798
Joza N, Susin SA, Daugas E, Stanford WL, Cho SK, Li CY, Sasaki T, Elia AJ, Cheng HY, Ravagnan L, Ferri KF, Zamzami N, Wakeham A, Hakem R, Yoshida H, Kong YY, Mak TW, Zuniga-Pflucker JC, Kroemer G, Penninger JM (2001) Essential role of the mitochondrial apoptosis-inducing factor in programmed cell death. Nature 410(6828):549–554
Otera H, Ohsakaya S, Nagaura Z, Ishihara N, Mihara K (2005) Export of mitochondrial AIF in response to proapoptotic stimuli depends on processing at the intermembrane space. EMBO J 24(7):1375–1386
Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM, Mangion J, Jacotot E, Costantini P, Loeffler M, Larochette N, Goodlett DR, Aebersold R, Siderovski DP, Penninger JM, Kroemer G (1999) Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 397(6718):441–446
Xia Z, Dickens M, Raingeaud J, Davis RJ, Greenberg ME (1995) Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science 270(5240):1326–1331
Cobb MH (1999) MAP kinase pathways. Prog Biophys Mol Biol 71(3–4):479–500
Coffer PJ, Jin J, Woodgett JR (1998) Protein kinase B (c-Akt): a multifunctional mediator of phosphatidylinositol 3-kinase activation. Biochem J 335(Pt 1):1–13
Martin KA, Blenis J (2002) Coordinate regulation of translation by the PI 3-kinase and mTOR pathways. Adv Cancer Res 86:1–39
Le Tourneau C, Faivre S, Serova M, Raymond E (2008) mTORC1 inhibitors: is temsirolimus in renal cancer telling us how they really work? Br J Cancer 99(8):1197–1203
Foti C, Florean C, Pezzutto A, Roncaglia P, Tomasella A, Gustincich S, Brancolini C (2009) Characterization of caspase-dependent and caspase-independent deaths in glioblastoma cells treated with inhibitors of the ubiquitin-proteasome system. Mol Cancer Ther 8(11):3140–3150
Kitagawa H, Tani E, Ikemoto H, Ozaki I, Nakano A, Omura S (1999) Proteasome inhibitors induce mitochondria-independent apoptosis in human glioma cells. FEBS Lett 443(2):181–186
Yu C, Friday BB, Yang L, Atadja P, Wigle D, Sarkaria J, Adjei AA (2008) Mitochondrial Bax translocation partially mediates synergistic cytotoxicity between histone deacetylase inhibitors and proteasome inhibitors in glioma cells. Neuro Oncol 10(3):309–319
Wagenknecht B, Hermisson M, Groscurth P, Liston P, Krammer PH, Weller M (2000) Proteasome inhibitor-induced apoptosis of glioma cells involves the processing of multiple caspases and cytochrome c release. J Neurochem 75(6):2288–2297
Laurent N, de Bouard S, Guillamo JS, Christov C, Zini R, Jouault H, Andre P, Lotteau V, Peschanski M (2004) Effects of the proteasome inhibitor ritonavir on glioma growth in vitro and in vivo. Mol Cancer Ther 3(2):129–136
Roth P, Kissel M, Herrmann C, Eisele G, Leban J, Weller M, Schmidt F (2009) SC68896, a novel small molecule proteasome inhibitor, exerts antiglioma activity in vitro and in vivo. Clin Cancer Res 15(21):6609–6618
Gross A, McDonnell JM, Korsmeyer SJ (1999) BCL-2 family members and the mitochondria in apoptosis. Genes Dev 13(15):1899–1911
Tatton WG, Olanow CW (1999) Apoptosis in neurodegenerative diseases: the role of mitochondria. Biochim Biophys Acta 1410(2):195–213
Poppe M, Reimertz C, Dussmann H, Krohn AJ, Luetjens CM, Bockelmann D, Nieminen AL, Kogel D, Prehn JH (2001) Dissipation of potassium and proton gradients inhibits mitochondrial hyperpolarization and cytochrome c release during neural apoptosis. J Neurosci 21(13):4551–4563
Nowak G (2002) PKC-a and ERK1/2 mediate mitochondrial dysfunction, decreases in active Na+ transport, and cisplatin-induced apoptosis in renal cells. J Biol Chem 277:43377–43388
Ling YH, Liebes L, Zou Y, Perez-Soler R (2003) Reactive oxygen species generation and mitochondrial dysfunction in the apoptotic response to Bortezomib, a novel proteasome inhibitor, in human H460 non-small cell lung cancer cells. J Biol Chem 278(36):33714–33723
Papa L, Gomes E, Rockwell P (2007) Reactive oxygen species induced by proteasome inhibition in neuronal cells mediate mitochondrial dysfunction and a caspase-independent cell death. Apoptosis 12(8):1389–1405
Monney L, Otter I, Olivier R, Ozer HL, Haas AL, Omura S, Borner C (1998) Defects in the ubiquitin pathway induce caspase-independent apoptosis blocked by Bcl-2. J Biol Chem 273(11):6121–6131
Bhaskara VK, Sundaram C, Babu PP (2006) pERK, pAkt and pBad: a possible role in cell proliferation and sustained cellular survival during tumorigenesis and tumor progression in ENU induced transplacental glioma rat model. Neurochem Res 31(9):1163–1170
Jacques-Silva MC, Bernardi A, Rodnight R, Lenz G (2004) ERK, PKC and PI3 K/Akt pathways mediate extracellular ATP and adenosine-induced proliferation of U138-MG human glioma cell line. Oncology 67(5–6):450–459
Wang L, Liu F, Adamo ML (2001) Cyclic AMP inhibits extracellular signal-regulated kinase and phosphatidylinositol 3-kinase/Akt pathways by inhibiting Rap1. J Biol Chem 276(40):37242–37249
Ai Z, Yin L, Zhou X, Zhu Y, Zhu D, Yu Y, Feng Y (2006) Inhibition of survivin reduces cell proliferation and induces apoptosis in human endometrial cancer. Cancer 107(4):746–756
Yao LL, Wang YG, Cai WJ, Yao T, Zhu YC (2007) Survivin mediates the anti-apoptotic effect of delta-opioid receptor stimulation in cardiomyocytes. J Cell Sci 120(Pt 5):895–907
Mitchell C, Park MA, Zhang G, Yacoub A, Curiel DT, Fisher PB, Roberts JD, Grant S, Dent P (2007) Extrinsic pathway- and cathepsin-dependent induction of mitochondrial dysfunction are essential for synergistic flavopiridol and vorinostat lethality in breast cancer cells. Mol Cancer Ther 6(12 Pt 1):3101–3112
Faivre S, Kroemer G, Raymond E (2006) Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov 5(8):671–688
Karmakar S, Banik NL, Ray SK (2008) Combination of all-trans retinoic acid and paclitaxel-induced differentiation and apoptosis in human glioblastoma U87MG xenografts in nude mice. Cancer 112(3):596–607
Otera H, Ohsakaya S, Nagaura Z, Ishihara N, Mihara K (2005) Export of mitochondrial AIF in response to proapoptotic stimuli depends on processing at the intermembrane space. EMBO J 24(7):1375–1386
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Ko, J.K., Choi, C.H., Kim, Y.K. et al. The Proteasome Inhibitor MG-132 Induces AIF Nuclear Translocation Through Down-Regulation of ERK and Akt/mTOR Pathway. Neurochem Res 36, 722–731 (2011). https://doi.org/10.1007/s11064-010-0387-9
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11064-010-0387-9