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Bcl2L12 inhibits post-mitochondrial apoptosis signaling in glioblastoma

¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA; ² Center for Neuro-Oncology and Department of Neurology, Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA; ³ Center for Applied Cancer Science and the Belfer Foundation Institute for Innovative Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA; ⁴ Department of Pathology, Cancer Center and Neurosurgical Service, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA; ⁵ Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA; ⁶ Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA; ⁷ Department of Medicine and Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA; ⁸ Department of Dermatology, Harvard Medical School, Boston, Massachusetts 02115, USA

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.

[Keywords: Apoptosis; caspase-7; malignant glioma; necrosis]

Received August 9, 2006; revised version accepted November 14, 2006.

¹⁰ Corresponding authors.

E-MAIL lynda_chin{at}dfci.harvard.edu; FAX (617) 582-8169.

¹¹ E-MAIL ron_depinho{at}dfci.harvard.edu; FAX (617) 632-6069.

Supplemental material is available at http://www.genesdev.org.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1480007

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