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Disruption of the VDAC2-Bak interaction by Bcl-x(S) mediates efficient induction of apoptosis in melanoma cells

Item Type:Article
Title:Disruption of the VDAC2-Bak interaction by Bcl-x(S) mediates efficient induction of apoptosis in melanoma cells
Creators Name:Ploetz, M. and Gillissen, B. and Hossini, A.M. and Daniel, P.T. and Eberle, J.
Abstract:The proapoptotic B-cell lymphoma (Bcl)-2 protein Bcl-x(S) encloses the Bcl-2 homology (BH) domains BH3 and BH4 and triggers apoptosis via the multidomain protein Bak, however, the mechanism remained elusive. For investigating Bcl-x(S) efficacy and pathways, an adenoviral vector was constructed with its cDNA under tetracycline-off control. Bcl-x(S) overexpression resulted in efficient apoptosis induction and caspase activation in melanoma cells. Indicative of mitochondrial apoptosis pathways, Bcl-x(S) translocated to the mitochondria, disrupted the mitochondrial membrane potential and induced release of cytochrome c, apoptosis-inducing factor and second mitochondria-derived activator of caspases. In melanoma cells, Bcl-x(S) resulted in significant Bak activation, and Bak knockdown as well as Bcl-x(L) overexpression abrogated Bcl-x(S)-induced apoptosis, whereas Mcl-1 (myeloid cell leukemia-1) knockdown resulted in a sensitization. With regard to the particular role of voltage-dependent anion channel 2 (VDAC2) for inhibition of Bak, we identified here a notable interaction between Bcl-x(S) and VDAC2 in melanoma cells, which was proven in reciprocal coimmunoprecipitation analyses. On the other hand, Bcl-x(S) showed no direct interaction with Bak, and its binding to VDAC2 appeared as also independent of Bak expression. Suggesting a new proapoptotic mechanism, Bcl-x(S) overexpression resulted in disruption of the VDAC2-Bak interaction leading to release of Bak. Further supporting this pathway, overexpression of VDAC2 strongly decreased apoptosis by Bcl-x(S). New proapoptotic pathways are of principle interest for overcoming apoptosis deficiency of melanoma cells.
Keywords:Bcl-xS, Bak, VDAC2, Melanoma, Apoptosis
Source:Cell Death and Differentiation
ISSN:1350-9047
Publisher:Nature Publishing Group (U.K.)
Volume:19
Number:12
Page Range:1928-1938
Date:December 2012
Official Publication:https://doi.org/10.1038/cdd.2012.71
PubMed:View item in PubMed

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