Prognostic impact of the expression/phosphorylation of the BH3-only proteins of the BCL-2 family in glioblastoma multiforme

P F Cartron,M Campone,F M Vallette,D Loussouarn,S A Martin

doi:10.1038/cddis.2012.150

Abstract

Apoptosis has a crucial role in anti-cancer treatment. The proteins of the BCL-2 family are core members of the apoptotic program. Thus, we postulated that alterations in the expression of BCL-2 protein family, and in particular in that of the Bcl-2 homology domain 3 (BH3)-only proteins (which can neutralized anti-apoptotic proteins or activate pro-apoptotic proteins) could account for differences in the overall survival (OS) of patients. To test this hypothesis, we analyzed the expression of 15 members of the BCL-2 protein family (Bax, Bak, Bok, Bcl-2, Bcl-xl, Bcl-w, Mcl-1, Bad, Bid, Bim, Bik, Bmf, Hrk, Noxa and Puma) in glioblastoma multiforme (GBM) tumors, the most frequent brain tumor in adults. We found that none of the individual expression of these proteins is associated with a significant variation in OS of the patients. However, when all BH3 proteins were pooled to determine a BH3score, this score was significantly correlated with OS of GBM patients. We also noted that patients with a have high level of phospho-Bad and phospho-Bim displayed a lower OS. Thus, BH3 scoring/profiling could be used as an independent prognostic factor in GBM when globally analyzed.

Highlights

The BCL-2 family of proteins appears to be central in both the initiation and execution of apoptosis, which is composed of three subgroups: the anti-apoptotic proteins, the multi-domain pro-apoptotic proteins and the Bcl-2 homology domain 3 (BH3)-only pro-apoptotic proteins (Figure 1).[6]
We monitored the expression of 13 members of the BCL-2 protein family (Bax, Bak, Bok, Bcl-2, Bcl-xl, Bcl-w, Mcl-1, Bad, Bid, Bik, Bim, Bmf, Hrk, Noxa and Puma) in 10 glioblastoma multiforme (GBM) using western blotting (WB) and ELISAs (Figure 1b)
By analyzing the 10 GBM, we observed that the ratio between the maximal and minimal value of expression was inferior to three for the Mcl-1, Bmf, Bik and Bok proteins and was superior to three for the other members of the BCL-2 protein family (Figure 1c)

Summary

Introduction

The BCL-2 family of proteins appears to be central in both the initiation and execution of apoptosis, which is composed of three subgroups: the anti-apoptotic proteins, the multi-domain pro-apoptotic proteins and the Bcl-2 homology domain 3 (BH3)-only pro-apoptotic proteins (Figure 1).[6]. Several papers have been devoted to the analyses of the interactions between proand anti-apoptotic proteins, and in particular, between the BH3-only proteins and the anti-apoptotic proteins and their putative relationships to the response to anti-cancer treatment.[10] it has been shown that this ‘BH3 profiling’ can predict sensitivity to conventional chemotherapeutic agents such as etoposide, vincristine and adriamycin. Expression level of members of the BCL-2 family of proteins appears to be a marker of the therapeutic response and/or of the clinico-pathological characteristic in some cancers.[11,12,13]. Posttranslational modification of the function of BCL-2 family of proteins, and in particular, the pro-apoptotic function of the Bad and Bim, both pro-apoptotic proteins, were investigated by determining the phosphorylation of these proteins in conjunction with a variation in OS in GBM patients.[14]

Methods

Results

Conclusion