Bim is the key mediator of glucocorticoid-induced apoptosis and of its potentiation by rapamycin in human myeloma cells

Biochimica Et Biophysica Acta
Nuria López-RoyuelaJavier Naval

Abstract

Glucocorticoids are widely used in anti-myeloma therapy and their action is potentiated by rapamycin, a mTOR inhibitor. However, the molecular mechanisms underlying these effects remain poorly characterized. We show here that dexamethasone (Dex)-induced apoptosis in MM.1S and OPM-2 cells is characterized by Bax and Bak conformational changes, DeltaPsi(m) loss, cytochrome c release and caspase-3 activation. Rapamycin, which had minimal cytotoxic effect by itself, strongly potentiated Dex-induced apoptosis. Apoptotic gene expression profiling showed an increase in mRNA levels of Bim in MM.1S cells after Dex treatment and further increases in both cell lines when co-treated with rapamycin. Western blot analysis revealed a moderate increase in Bim protein levels in both MM.1S and OPM-2 cells. Immunoprecipitation experiments revealed that most Bim was complexed to Mcl-1 in untreated cells. Upon treatment with Dex, and specially Dex plus rapamycin, Bim-Mcl-1 complex was disrupted and Bim was found associated to a CHAPS-insoluble fraction. Overexpression of Mcl-1 stabilized Bim-Mcl-1 complexes upon treatment with Dex or Dex+rapamycin and fully prevented apoptosis. Gene silencing of Bim inhibited for the most part Dex-induced apoptosis...Continue Reading

References

Feb 1, 1988·The Journal of Clinical Investigation·A R McDonald, I D Goldfine
Dec 31, 1997·The Journal of Biological Chemistry·D ChauhanK Anderson
Feb 28, 1998·The EMBO Journal·L O'ConnorD C Huang
Feb 19, 1999·Lancet·G Gahrton
May 18, 2001·The Journal of Biological Chemistry·D ChauhanK C Anderson
Jun 20, 2003·Cell Death and Differentiation·N J Waterhouse, J A Trapani
Mar 12, 2004·The Journal of Biological Chemistry·Jie HanHannah Rabinowich
Apr 9, 2004·Blood·Thomas StrömbergHelena Jernberg-Wiklund
May 13, 2004·The Journal of Biological Chemistry·Oihana TerronesGorka Basañez
Oct 2, 2004·European Journal of Immunology·Patricia Gomez-BougieMartine Amiot
Nov 23, 2006·Nature Cell Biology·Hyungjin KimEmily H-Y Cheng
Feb 20, 2007·Archives of Biochemistry and Biophysics·Georg Häcker, Arnim Weber
Mar 17, 2007·Molecular Cancer Therapeutics·Rafael Fonseca, A Keith Stewart
Aug 8, 2007·Biochemical and Biophysical Research Communications·Soraya Wuillème-ToumiMartine Amiot

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Citations

Feb 23, 2013·ISRN Hematology·Ronit Vogt Sionov
Dec 24, 2018·The Journal of Immunology : Official Journal of the American Association of Immunologists·Benedikt JacobsKarl-Johan Malmberg
Sep 26, 2015·Oncotarget·Ronit Vogt SionovZvi Granot
Jan 22, 2013·Molecular Pharmaceutics·Diego De MiguelLuis Martinez-Lostao

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