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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Hallmarks of Cancer: The Next Generation
Hanahan, D., & Weinberg, R. A. (2011) · Cell · doi:10.1016/j.cell.2011.02.013 · Cited by 66,590
Hengartner, M. O. (2000) · Nature · doi:10.1038/35037710 · Cited by 5,779
Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery
Datta, S. R., Dudek, H., Tao, X., Masters, S., Fu, H., Gotoh, Y., & Greenberg, M. E. (1997) · Cell · doi:10.1016/s0092-8674(00)80405-5 · Cited by 5,689
Proapoptotic BAX and BAK: A Requisite Gateway to Mitochondrial Dysfunction and Death
Wei, M. C., Zong, W.-X., Cheng, E. H.-Y., Lindsten, T., Panoutsakopoulou, V., Ross, A. J., Roth, K. A., MacGregor, G. R., Thompson, C. B., & Korsmeyer, S. J. (2001) · Science · doi:10.1126/science.1059108 · Cited by 3,988
PUMA, a Novel Proapoptotic Gene, Is Induced by p53
Nakano, K., & Vousden, K. H. (2001) · Molecular Cell · doi:10.1016/s1097-2765(01)00214-3 · Cited by 2,315
The Bcl-2 apoptotic switch in cancer development and therapy
Adams, J. M., & Cory, S. (2007) · Oncogene · doi:10.1038/sj.onc.1210220 · Cited by 2,256
Goldberg, R. M., Sargent, D. J., Morton, R. F., Fuchs, C. S., Ramanathan, R. K., Williamson, S. K., Findlay, B., Pitot, H. C., & Alberts, S. R. (2003) · Journal of Clinical Oncology · doi:10.1200/jco.2004.09.046 · Cited by 2,251
Chen, L., Willis, S. N., Wei, A., Smith, B. J., Fletcher, J. I., Hinds, M. G., Colman, P. M., Day, C. L., Adams, J. M., & Huang, D. C. S. (2005) · Molecular Cell · doi:10.1016/j.molcel.2004.12.030 · Cited by 1,816
p53- and Drug-Induced Apoptotic Responses Mediated by BH3-Only Proteins Puma and Noxa
Villunger, A., Michalak, E. M., Coultas, L., Müllauer, F., Böck, G., Ausserlechner, M. J., Adams, J. M., & Strasser, A. (2003) · Science · doi:10.1126/science.1090072 · Cited by 1,327
Certo, M. V., Moore, V. D. G., Nishino, M., Wei, G., Korsmeyer, S. J., Armstrong, S. A., & Letai, A. G. (2006) · Cancer Cell · doi:10.1016/j.ccr.2006.03.027 · Cited by 1,278
van Delft, M. F., Wei, A. H., Mason, K. D., Vandenberg, C. J., Chen, L., Czabotar, P. E., Willis, S. N., Scott, C. L., Day, C. L., Cory, S., et al. (2006) · Cancer Cell · doi:10.1016/j.ccr.2006.08.027 · Cited by 1,271
Induction of Apoptosis by Cancer Chemotherapy
Kaufmann, S. H., & Earnshaw, W. C. (2000) · Experimental Cell Research · doi:10.1006/excr.2000.4838 · Cited by 1,266
Trends in Risks Associated With New Drug Development: Success Rates for Investigational Drugs
DiMasi, J. A., Feldman, L., Seckler, A., & Wilson, A. (2010) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.2009.295 · Cited by 866
Puthalakath, H., Villunger, A., O'Reilly, L. A., Beaumont, J. G., Coultas, L., Cheney, R. E., Huang, D. C. S., & Strasser, A. (2001) · Science · doi:10.1126/science.1062257 · Cited by 656
BCL-2 family antagonists for cancer therapy
Lessène, G., Czabotar, P. E., & Colman, P. M. (2008) · Nature Reviews Drug Discovery · doi:10.1038/nrd2658 · Cited by 639
A Unified Model of Mammalian BCL-2 Protein Family Interactions at the Mitochondria
Llambi, F., Moldoveanu, T., Tait, S. W. G., Bouchier-Hayes, L., Temirov, J., McCormick, L. L., Dillon, C. P., & Green, D. R. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.10.001 · Cited by 596
Self-citationPretreatment Mitochondrial Priming Correlates with Clinical Response to Cytotoxic Chemotherapy
Chonghaile, T. N., Sarosiek, K. A., Vo, T.-T. T., Ryan, J. A., Tammareddi, A., Moore, V. D. G., Deng, J., Anderson, K. C., Richardson, P. G. G., Tai, Y., et al. (2011) · Science · doi:10.1126/science.1206727 · Cited by 588
Apoptosis defects and chemotherapy resistance: molecular interaction maps and networks
Pommier, Y. G., Sordet, O., Antony, S., Hayward, R. L., & Kohn, K. W. (2004) · Oncogene · doi:10.1038/sj.onc.1207515 · Cited by 563
Antioxidant and pro-oxidant actions of the plant phenolics quercetin, gossypol and myricetin
Laughton, M. J., Halliwell, B. B., Evans, P., Robin, J., & Hoult, S. (1989) · Biochemical Pharmacology · doi:10.1016/0006-2952(89)90442-5 · Cited by 559
Sunters, A., Fernández de Mattos, S., Stahl, M., Brosens, J. J., Zoumpoulidou, G., Saunders, C. A., Coffer, P. J., Medema, R. H., Coombes, R. C., & Lam, E. W.-F. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m309523200 · Cited by 505
Embedded together: The life and death consequences of interaction of the Bcl-2 family with membranes
Leber, B. F., Lin, J., & Andrews, D. W. (2007) · APOPTOSIS · doi:10.1007/s10495-007-0746-4 · Cited by 378
Quantitative Analysis of Pathways Controlling Extrinsic Apoptosis in Single Cells
Albeck, J. G., Burke, J. M., Aldridge, B. B., Zhang, M., Lauffenburger, D. A., & Sorger, P. K. (2008) · Molecular Cell · doi:10.1016/j.molcel.2008.02.012 · Cited by 377
BCL2A1: the underdog in the BCL2 family
Vogler, M. (2011) · Cell Death and Differentiation · doi:10.1038/cdd.2011.158 · Cited by 340
Up-regulation of Bcl-2 Homology 3 (BH3)-only Proteins by E2F1 Mediates Apoptosis
Hershko, T., & Ginsberg, D. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m312866200 · Cited by 322
Hennessy, B. T., Lu, Y., Gonzalez-Angulo, A. M., Carey, M. S., Myhre, S., Ju, Z., Davies, M. A., Liu, W., Coombes, K. R., Meric‐Bernstam, F., et al. (2010) · Clinical Proteomics · doi:10.1007/s12014-010-9055-y · Cited by 241
Rehm, M., Huber, H. J., Düßmann, H., & Prehn, J. H. M. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601295 · Cited by 209
Self-citationDifferent forms of cell death induced by putative BCL2 inhibitors
Vogler, M., Weber, K., Dinsdale, D. D., Schmitz, I., Schulze‐Osthoff, K., Dyer, M. J. S., & Cohen, G. M. (2009) · Cell Death and Differentiation · doi:10.1038/cdd.2009.48 · Cited by 203
Molecular Details of Bax Activation, Oligomerization, and Membrane Insertion
Bleicken, S., Classen, M., Padmavathi, P. V. L., Ishikawa, T., Zeth, K., Steinhoff, H., & Bordignon, E. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.081539 · Cited by 176
Drug development and clinical trials—the path to an approved cancer drug
Rubin, E. H., & Gilliland, D. G. (2012) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2012.22 · Cited by 135
Apoptosis signaling proteins as prognostic biomarkers in colorectal cancer: A review
Hector, S., & Prehn, J. H. M. (2009) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2008.12.002 · Cited by 128
Self-citationPrognostic value of bcl-2 oncoprotein expression in stage II colon carcinoma.
Sinicrope, F. A., Hart, J. A. L., Michelassi, F., & Lee, J. J. (1995) · PubMed · Cited by 123
Assembly of the Mitochondrial Apoptosis-induced Channel, MAC
Martinez‐Caballero, S., Dejean, L. M., Kinnally, M., Oh, K. J., Mannella, C. A., & Kinnally, K. W. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m806610200 · Cited by 115
Ekoff, M., Kaufmann, T., Engström, M., Motoyama, N., Villunger, A., Jönsson, J., Strasser, A., & Nilsson, G. P. (2007) · Blood · doi:10.1182/blood-2007-02-073957 · Cited by 114
Happo, L., Cragg, M. S., Phipson, B., Haga, J. M., Jansen, E. S., Herold, M. J., Dewson, G., Michalak, E. M., Vandenberg, C. J., Smyth, G. K., et al. (2010) · Blood · doi:10.1182/blood-2010-04-280818 · Cited by 112
Tissue expression and subcellular localization of the pro-survival molecule Bcl-w
O’Reilly, L. A., Print, C. G., Hausmann, G., Moriishi, K., Cory, S., Huang, D. C. S., & Strasser, A. (2001) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4400835 · Cited by 109
Düßmann, H., Rehm, M., Concannon, C. G., Anguissola, S., Würstle, M. L., Kacmar, S., Völler, P., Huber, H. J., & Prehn, J. H. M. (2009) · Cell Death and Differentiation · doi:10.1038/cdd.2009.123 · Cited by 101
Self-citationKrajewska, M., Kim, H., Kim, C., Kang, H., Welsh, K., Matsuzawa, S., Tsukamoto, M., Thomas, R. G., Assa‐Munt, N., Piao, Z. H., et al. (2005) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-05-0094 · Cited by 92
Wei, J., Kitada, S., Rega, M. F., Stebbins, J. L., Zhai, D., Cellitti, J. F., Yuan, H., Emdadi, A., Dahl, R. S., Zhang, Z., et al. (2009) · Journal of Medicinal Chemistry · doi:10.1021/jm900472s · Cited by 57
Kinetics of gossypol inhibition of bovine lactate dehydrogenase X
Olgiati, K. L., & Toscano, W. A. (1983) · Biochemical and Biophysical Research Communications · doi:10.1016/0006-291x(83)90986-5 · Cited by 56
Hector, S., Rehm, M., Schmid, J., Kehoe, J., McCawley, N., Dicker, P., Murray, F., McNamara, D. A., Kay, E. W., Concannon, C. G., et al. (2011) · Gut · doi:10.1136/gutjnl-2011-300433 · Cited by 54
Self-citationHuber, H. J., Düßmann, H., Kilbride, S. M., Rehm, M., & Prehn, J. H. M. (2011) · Molecular Systems Biology · doi:10.1038/msb.2011.2 · Cited by 53
Self-citationManne, U., Weiss, H. L., & Grizzle, W. E. (2000) · International Journal of Cancer · doi:10.1002/1097-0215(20000920)89:5 · Cited by 46
Mathematical modelling of the mitochondrial apoptosis pathway
Huber, H. J., Düßmann, H., Wenus, J., Kilbride, S. M., & Prehn, J. H. M. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2010.10.004 · Cited by 32
Self-citationHou, M. L., Morishita, Y., Iljima, T., Inadome, Y., Mase, K., Dai, Y., & Noguchi, M. (1999) · International Journal of Cancer · doi:10.1002/(sici)1097-0215(19991222)84:6 · Cited by 29
Schmid, J., Düßmann, H., Boukes, G. J., Flanagan, L., Lindner, A. U., O'Connor, C. L., Rehm, M., Prehn, J. H. M., & Huber, H. J. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.411827 · Cited by 28
Self-citationOncogenic KRAS sensitises colorectal tumour cells to chemotherapy by p53-dependent induction of Noxa
de Bruijn, M. T., Raats, D., Hoogwater, F. J. H., van Houdt, W. J., Cameron, K., Medema, J. P., Rinkes, I. H. M. B., & Kranenburg, O. (2010) · British Journal of Cancer · doi:10.1038/sj.bjc.6605633 · Cited by 26
Kubota, Y., Kinoshita, K., Suetomi, K., Fujimori, A., & Takahashi, S. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.178.5.2923 · Cited by 13
Cited by
Sorted by citations
Essential versus accessory aspects of cell death: recommendations of the NCCD 2015
Galluzzi, L., Bravo-San Pedro, J. M., Vitale, I., Aaronson, S. A., Abrams, J. M., Adam, D., Alnemri, E. S., Altucci, L., Andrews, D., Annicchiarico-Petruzzelli, M., et al. (2015) · Cell Death & Differentiation · doi:10.1038/cdd.2014.137 · Cited by 1,002
Self-citationMitochondria—Judges and Executioners of Cell Death Sentences
Bhola, P. D., & Letai, A. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.02.019 · Cited by 326
Decoding and unlocking the BCL-2 dependency of cancer cells
Juin, P. P., Geneste, O., Gautier, F., Depil, S., & Campone, M. (2013) · Nature reviews. Cancer · doi:10.1038/nrc3538 · Cited by 254
Akl, H., Vervloessem, T., Kiviluoto, S., Bittremieux, M., Parys, J. B., SMEDT, H. D., & Bultynck, G. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2014.04.017 · Cited by 225
From word models to executable models of signaling networks using automated assembly
Gyori, B. M., Bachman, J. A., Subramanian, K., Muhlich, J. L., Galescu, L., & Sorger, P. K. (2017) · Molecular Systems Biology · doi:10.15252/msb.20177651 · Cited by 188
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
