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Differential Apaf-1 levels allow cytochrome c to induce apoptosis in brain tumors but not in normal neural tissues.

Publication ,  Journal Article
Johnson, CE; Huang, YY; Parrish, AB; Smith, MI; Vaughn, AE; Zhang, Q; Wright, KM; Van Dyke, T; Wechsler-Reya, RJ; Kornbluth, S; Deshmukh, M
Published in: Proceedings of the National Academy of Sciences of the United States of America
December 2007

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.

Duke Scholars

Published In

Proceedings of the National Academy of Sciences of the United States of America

DOI

EISSN

1091-6490

ISSN

0027-8424

Publication Date

December 2007

Volume

104

Issue

52

Start / End Page

20820 / 20825

Related Subject Headings

  • Transcription, Genetic
  • Promoter Regions, Genetic
  • Oligonucleotide Array Sequence Analysis
  • Neurons
  • Medulloblastoma
  • Humans
  • Gene Expression Regulation, Neoplastic
  • E2F1 Transcription Factor
  • Cytochromes c
  • Caspases
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Johnson, C. E., Huang, Y. Y., Parrish, A. B., Smith, M. I., Vaughn, A. E., Zhang, Q., … Deshmukh, M. (2007). Differential Apaf-1 levels allow cytochrome c to induce apoptosis in brain tumors but not in normal neural tissues. Proceedings of the National Academy of Sciences of the United States of America, 104(52), 20820–20825. https://doi.org/10.1073/pnas.0709101105
Johnson, Carrie E., Yolanda Y. Huang, Amanda B. Parrish, Michelle I. Smith, Allyson E. Vaughn, Qian Zhang, Kevin M. Wright, et al. “Differential Apaf-1 levels allow cytochrome c to induce apoptosis in brain tumors but not in normal neural tissues.Proceedings of the National Academy of Sciences of the United States of America 104, no. 52 (December 2007): 20820–25. https://doi.org/10.1073/pnas.0709101105.
Johnson CE, Huang YY, Parrish AB, Smith MI, Vaughn AE, Zhang Q, et al. Differential Apaf-1 levels allow cytochrome c to induce apoptosis in brain tumors but not in normal neural tissues. Proceedings of the National Academy of Sciences of the United States of America. 2007 Dec;104(52):20820–5.
Johnson, Carrie E., et al. “Differential Apaf-1 levels allow cytochrome c to induce apoptosis in brain tumors but not in normal neural tissues.Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 52, Dec. 2007, pp. 20820–25. Epmc, doi:10.1073/pnas.0709101105.
Johnson CE, Huang YY, Parrish AB, Smith MI, Vaughn AE, Zhang Q, Wright KM, Van Dyke T, Wechsler-Reya RJ, Kornbluth S, Deshmukh M. Differential Apaf-1 levels allow cytochrome c to induce apoptosis in brain tumors but not in normal neural tissues. Proceedings of the National Academy of Sciences of the United States of America. 2007 Dec;104(52):20820–20825.
Journal cover image

Published In

Proceedings of the National Academy of Sciences of the United States of America

DOI

EISSN

1091-6490

ISSN

0027-8424

Publication Date

December 2007

Volume

104

Issue

52

Start / End Page

20820 / 20825

Related Subject Headings

  • Transcription, Genetic
  • Promoter Regions, Genetic
  • Oligonucleotide Array Sequence Analysis
  • Neurons
  • Medulloblastoma
  • Humans
  • Gene Expression Regulation, Neoplastic
  • E2F1 Transcription Factor
  • Cytochromes c
  • Caspases