The Proteasome Inhibitor MG-132 Induces AIF Nuclear Translocation Through Down-Regulation of ERK and Akt/mTOR Pathway
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.
KeywordsApoptosis AIF Caspase-independent Down-regulation of ERK and Akt/mTOR Human glioma cells
- 7.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, 945–952Google Scholar
- 11.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):549–554PubMedCrossRefGoogle Scholar
- 13.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):441–446PubMedCrossRefGoogle Scholar
- 19.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):3140–3150PubMedCrossRefGoogle Scholar
- 37.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):3101–3112PubMedCrossRefGoogle Scholar