Bcl2L12 inhibits post-mitochondrial apoptosis signaling in glioblastoma.
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.
Stegh
Alexander H
AH
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Kim
Hyunggee
H
Bachoo
Robert M
RM
Forloney
Kristin L
KL
Zhang
Jean
J
Schulze
Harald
H
Park
Kevin
K
Hannon
Gregory J
GJ
Yuan
Junying
J
Louis
David N
DN
DePinho
Ronald A
RA
Chin
Lynda
L
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D053478:Apoptosomes; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D001932:Brain Neoplasms / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004789:Enzyme Activation; D005909:Glioblastoma / Q000378:metabolism*; D005910:Glioma / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D008928:Mitochondria / Q000378:metabolism*; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009336:Necrosis; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D011817:Rabbits; D015398:Signal Transduction
D051017:Apoptosis Regulatory Proteins; D053478:Apoptosomes; C430100:BCL2L12 protein, human; C101155:Bcl2l2 protein, mouse; D007074:Immunoglobulin G; D009124:Muscle Proteins; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D045304:Cytochromes c; D053179:Caspase 7; D053453:Caspase 9