The expression of a new variant of the pro-apoptotic molecular Bax, Baxψ, is correlated with an increased survival of glioblastoma multiforme patients

Abstract

Pro- and anti-apoptotic members of the BCL-2 family play a central role in the implementation of apoptosis. Bax, a pro-apoptotic member of this family, has as such been considered as a potential tumor suppressor. Here, we have examined the expression of Bax in 55 patients with glioblastoma multiforme (GMB), the most common and aggressive form of brain tumors. We report on the existence of a new form of Bax, present in 24% of the patients, which we called Baxψ. Baxψ is a N-terminal truncated form of Bax which results from a partial deletion of the exon 1 of Bax gene. Baxψ and the wild-type form, Baxα, are encoded by distinct mRNAs, both of which are present in normal tissues. Glial tumors express either Baxα or Baxψ proteins, an apparent consequence of an exclusive transcription of the corresponding mRNAs. The latter feature could be partially linked to distinct methylation profiles of Bax gene in these tumors. The Baxψ protein is preferentially localized to mitochondria and is a more powerful inducer of apoptosis than Baxα. Baxψ tumors exhibit a slow proliferation in Swiss nude mice and this feature can be circumvented by the co-expression of the Bcl-2 transgene, the functional antagonist of Bax. More importantly, the expression of Baxψ correlates with a longer survival in patients (18 months versus 10 months for Baxα patients). Thus, our results provide the first indication of a beneficial involvement of a variant of the pro-apoptotic protein Bax in tumor progression.