Abstract
Glioblastoma (GBM) is the most common type of primary brain cancer and carries a dismal prognosis primarily due to the emergence of resistance towards extant radiation, conventional and targeted chemotherapies. Although GBM resists therapy-induced apoptosis, tumors show a seemingly paradoxical propensity for florid intratumoral necrogenesis. This necrosis manifests pathologically as microscopic foci or confluent expanses of necrotic tumor. While it is now well recognized that necrosis is an active cell death process and that apoptosis and necrosis death modalities are intertwined on multiple levels, the precise molecular mechanisms and genetic elements underlying these forms of cell death in GBM remain areas of active investigation. In recent oncogenomic studies, we identified a novel GBM oncoprotein, Bcl2-Like 12 (Bcl2L12), which is significantly expressed in the majority of primary GBM tumor specimens and distantly related to canonical Bcl-2 proteins. Due to its distinctive impact on cell death signaling, Bcl2L12 phenocopies pro-necrotic and anti-apoptotic propensities of high-grade glioma: Mechanistically, we determined that unlike prototypic Bcl-2 family members, Bcl2L12 does not safeguard mitochondrial membrane integrity, but instead potently inhibits apoptosis at the level of post-mitochondrial effector caspase-3/7 activation. A combination of enforced expression, RNAi-mediated extinction, co-localization and protein interaction studies revealed that Bcl2L12 inhibits caspases 3 and 7 via distinct mechanisms. Direct physical interaction underlies Bcl2L12's inhibition of caspase-7 processing, whereas Bcl2L12-induced transcriptional upregulation of the small heat shock protein αB-crystallin is instrumental to neutralization of caspase-3 activation. Mirroring the cellular phenotype elicited by energy depletion, genetic or pharmacologic inhibition of post-mitochondrial apoptosis signaling molecules, Bcl2L12 promotes necrogenesis in glial cells in the context of a proapoptotic stimulus establishing that it represents a novel regulator of the balance between apoptosis and necrosis in GBM.
Original language | English (US) |
---|---|
Pages (from-to) | 2833-2839 |
Number of pages | 7 |
Journal | Cell Cycle |
Volume | 7 |
Issue number | 18 |
DOIs | |
State | Published - Sep 15 2008 |
Funding
This work was supported by a Claudia-Adams Barr and a NIH K99/R00 (K99CA129172) award (AHS), NIH grants PO1 CA57683 (DNL) and CA95616 (RAD, DNL T DISTRIBUTEthe Bernard A. and Wendy J. Goldhirsh and LC), RO1 CA099041 (LC) and RO1 Foundation and the Christopher Elliot Foundation (RAD and LC). RAD is an American Cancer Society Research Professor and supported by the Robert A. and Renee E. Belfer Foundation Institute
Keywords
- Apoptosis
- Bcl2L12
- Caspase-3 and caspase-7
- Glioblastoma
- Necrosis
- αB-crystallin
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology
- Developmental Biology