The DOI matches its Crossref record; 47 of the 48 references it cites were found in a registry or an index.
Systems Analysis of BCL2 Protein Family Interactions Establishes a Model to Predict Responses to Chemotherapy
Open accessPublished version of a preprint
Abstract
Apoptotic desensitization is a hallmark of cancer cells, but present knowledge of molecular systems controlling apoptosis has yet to provide significant prognostic insights. Here, we report findings from a systems study of the intrinsic pathway of apoptosis by BCL2 family proteins and clinical translation of its findings into a model with applications in colorectal cancer (CRC). By determining absolute protein quantifications in CRC cells and patient tumor samples, we found that BAK and BAX were expressed more highly than their antiapoptotic inhibitors. This counterintuitive finding suggested that sole inhibition of effector BAX and BAK could not be sufficient for systems stability in nonstressed cells. Assuming a model of direct effector activation by BH3-only proteins, we calculated that the amount of stress-induced BH3-only proteins required to activate mitochondrial apoptosis could predict individual death responses of CRC cells to 5-fluorouracil/oxaliplatin. Applying this model predictor to protein profiles in tumor and matched normal tissue samples from 26 patients with CRCs, we found that differences in protein quantities were sufficient to model the increased tumor sensitivity to chemotherapy compared with normal tissue. In addition, these differences were sufficient to differentiate clinical responders from nonresponders with high confidence. Applications of our model, termed DR_MOMP, were used to assess the impact of apoptosis-sensitizing dugs in lowering the necessary dose of state-of-the-art chemotherapy in individual patients. Together, our findings offer a ready clinical tool with the potential to tailor chemotherapy to individual patients. Cancer Res; 73(2); 519–28. ©2012 AACR.
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Self-citationMitochondria—Judges and Executioners of Cell Death Sentences
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Decoding and unlocking the BCL-2 dependency of cancer cells
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From word models to executable models of signaling networks using automated assembly
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Metadata
- Authors
- Lindner, A. U., Concannon, C. G., Boukes, G. J., Cannon, M. D., Llambi, F., Ryan, D., Boland, K., Kehoe, J., McNamara, D. A., Murray, F., Kay, E. W., Hector, S., Green, D. R., Huber, H. J., & Prehn, J. H. M.
- Affiliations
- St. Jude Children's Research Hospital (US)
- Corresponding author
- Huber, Heinrich J.
- Prehn, Jochen H.M.
- ORCID
- Venue
- Cancer Research
- Published
- 2013-01-15
- Volume
- 73
- Issue
- 2
- Pages
- 519-528
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W1977323318
- Cited by
- 105
- References
- 48
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 4 · 2023: 8 · 2022: 7 · 2021: 15 · 2020: 5 · 2019: 8 · 2018: 6 · 2017: 8 · 2016: 15 · 2015: 7 · 2014: 9 · 2013: 8
- FWCI
- 5.82
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Lirias (submittedVersion, other-oa)
- Funders
- Johns Hopkins University
- European Commission
- Higher Education Authority
- Science Foundation Ireland
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- Bcl-2 family proteins, mitochondrial apoptosis, colorectal cancer, chemotherapy response prediction, Bak, Bax, BH3-only proteins, 5-fluorouracil, oxaliplatin, personalized chemotherapy, absolute protein quantification
- MeSH terms
- Aged, Antineoplastic Agents, Female, Humans, Male, Models, Biological, Systems Analysis, Colorectal Neoplasms, Treatment Outcome, Apoptosis, Proto-Oncogene Proteins c-bcl-2, Computational Biology, Protein Array Analysis, Cell Line, Tumor, bcl-2 Homologous Antagonist-Killer Protein, bcl-2-Associated X Protein
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