Differential Apaf-1 levels allow cytochrome c to induce apoptosis in brain tumors but not in normal neural tissues.
Abstract
Brain tumors are typically resistant to conventional chemotherapeutics, most of which
initiate apoptosis upstream of mitochondrial cytochrome c release. In this study,
we demonstrate that directly activating apoptosis downstream of the mitochondria,
with cytosolic cytochrome c, kills brain tumor cells but not normal brain tissue.
Specifically, cytosolic cytochrome c is sufficient to induce apoptosis in glioblastoma
and medulloblastoma cell lines. In contrast, primary neurons from the cerebellum and
cortex are remarkably resistant to cytosolic cytochrome c. Importantly, tumor tissue
from mouse models of both high-grade astrocytoma and medulloblastoma display hypersensitivity
to cytochrome c when compared with surrounding brain tissue. This differential sensitivity
to cytochrome c is attributed to high Apaf-1 levels in the tumor tissue compared with
low Apaf-1 levels in the adjacent brain tissue. These differences in Apaf-1 abundance
correlate with differences in the levels of E2F1, a previously identified activator
of Apaf-1 transcription. ChIP assays reveal that E2F1 binds the Apaf-1 promoter specifically
in tumor tissue, suggesting that E2F1 contributes to the expression of Apaf-1 in brain
tumors. Together, these results demonstrate an unexpected sensitivity of brain tumors
to postmitochondrial induction of apoptosis. Moreover, they raise the possibility
that this phenomenon could be exploited therapeutically to selectively kill brain
cancer cells while sparing the surrounding brain parenchyma.
Type
Journal articleSubject
ApoptosisApoptotic Protease-Activating Factor 1
Astrocytoma
Brain
Brain Neoplasms
Caspases
Cytochromes c
E2F1 Transcription Factor
Gene Expression Regulation, Neoplastic
Humans
Medulloblastoma
Neurons
Oligonucleotide Array Sequence Analysis
Promoter Regions, Genetic
Transcription, Genetic
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https://hdl.handle.net/10161/8392Published Version (Please cite this version)
10.1073/pnas.0709101105Publication Info
Johnson, Carrie E; Huang, Yolanda Y; Parrish, Amanda B; Smith, Michelle I; Vaughn,
Allyson E; Zhang, Qian; ... Deshmukh, Mohanish (2007). Differential Apaf-1 levels allow cytochrome c to induce apoptosis in brain tumors
but not in normal neural tissues. Proc Natl Acad Sci U S A, 104(52). pp. 20820-20825. 10.1073/pnas.0709101105. Retrieved from https://hdl.handle.net/10161/8392.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Sally A. Kornbluth
Jo Rae Wright University Distinguished Professor Emerita
Our lab studies the regulation of complex cellular processes, including cell cycle
progression and programmed cell death (apoptosis). These tightly orchestrated processes
are critical for appropriate cell proliferation and cell death, and when they go awry
can result in cancer and degenerative disorders. Within these larger fields, we have
focused on understanding the cellular mechanisms that prevent the onset of mitosis
prior to the completion of DNA replication, the process

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