Bcl2L12 inhibits post-mitochondrial apoptosis signaling in glioblastoma

Alexander H. Stegh, Hyunggee Kim, Robert M. Bachoo, Kristin L. Forloney, Jean Zhang, Harald Schulze, Kevin Park, Gregory J. Hannon, Junying Yuan, David N. Louis, Ronald A. DePinho*, Lynda Chin

*Corresponding author for this work

Research output: Contribution to journalArticle

104 Scopus citations

Abstract

Glioblastoma (GBM) is an astrocytic brain tumor characterized by an aggressive clinical course and intense resistance to all therapeutic modalities. Here, we report the identification and functional characterization of Bcl2L12 (Bcl2-like-12) that is robustly expressed in nearly all human primary GBMs examined. Enforced Bcl2L12 expression confers marked apoptosis resistance in primary cortical astrocytes, and, conversely, its RNA interference (RNAi)-mediated knockdown sensitizes human glioma cell lines toward apoptosis in vitro and impairs tumor growth with increased intratumoral apoptosis in vivo. Mechanistically, Bcl2L12 expression does not affect cytochrome c release or apoptosome-driven caspase-9 activation, but instead inhibits post-mitochondrial apoptosis signaling at the level of effector caspase activation. One of Bcl2L12's mechanisms of action stems from its ability to interact with and neutralize caspase-7. Notably, while enforced Bcl2L12 expression inhibits apoptosis, it also engenders a pronecrotic state, which mirrors the cellular phenotype elicited by genetic or pharmacologic inhibition of post-mitochondrial apoptosis molecules. Thus, Bcl2L12 contributes to the classical tumor biological features of GBM such as intense apoptosis resistance and florid necrosis, and may provide a target for enhanced therapeutic responsiveness of this lethal cancer.

Original languageEnglish (US)
Pages (from-to)98-111
Number of pages14
JournalGenes and Development
Volume21
Issue number1
DOIs
StatePublished - Jan 1 2007

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Keywords

  • Apoptosis
  • Caspase-7
  • Malignant glioma
  • Necrosis

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

Stegh, A. H., Kim, H., Bachoo, R. M., Forloney, K. L., Zhang, J., Schulze, H., Park, K., Hannon, G. J., Yuan, J., Louis, D. N., DePinho, R. A., & Chin, L. (2007). Bcl2L12 inhibits post-mitochondrial apoptosis signaling in glioblastoma. Genes and Development, 21(1), 98-111. https://doi.org/10.1101/gad.1480007