The DOI matches its Crossref record; 3 of the 3 references it cites were found in a registry or an index.
Targeting cap-dependent translation blocks converging survival signals by AKT and PIM kinases in lymphoma
Open accessAbstract
New anticancer drugs that target oncogenic signaling molecules have greatly improved the treatment of certain cancers. However, resistance to targeted therapeutics is a major clinical problem and the redundancy of oncogenic signaling pathways provides back-up mechanisms that allow cancer cells to escape. For example, the AKT and PIM kinases produce parallel oncogenic signals and share many molecular targets, including activators of cap-dependent translation. Here, we show that PIM kinase expression can affect the clinical outcome of lymphoma chemotherapy. We observe the same in animal lymphoma models. Whereas chemoresistance caused by AKT is readily reversed with rapamycin, PIM-mediated resistance is refractory to mTORC1 inhibition. However, both PIM- and AKT-expressing lymphomas depend on cap-dependent translation, and genetic or pharmacological blockade of the translation initiation complex is highly effective against these tumors. The therapeutic effect of blocking cap-dependent translation is mediated, at least in part, by decreased production of short-lived oncoproteins including c-MYC, Cyclin D1, MCL1, and the PIM1/2 kinases themselves. Hence, targeting the convergence of oncogenic survival signals on translation initiation is an effective alternative to combinations of kinase inhibitors.
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.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
TORC1 inhibition, via loss of 4EBP1 phosphorylation, results in a decrease of MCL-1 protein expression in some cancers.
“TORC1 inhibition, via loss of 4EBP1 (also referred to as EIF4EBP1) phosphorylation, results in a decrease of MCL-1 protein expression in these cancers (37–40).”
From mTOR Inhibition Specifically Sensitizes Colorectal Cancers with KRAS or BRAF Mutations to BCL-2/BCL-XL Inhibition by Suppressing MCL-1 (2014) · cites this paper as [40]
In Results and Discussion (page unavailable), the paper reports that rapamycin-sensitive lymphoma cells show changes in 4E-BP1 phosphorylation and cap-dependent translation under mTORC1 inhibition. The same section reports a loss of MCL1 protein after treatment with silvestrol, a direct translation inhibitor, but does not show that mTORC1 inhibition causes MCL1 loss through reduced 4E-BP1 phosphorylation. (LLM, conf=0.87)
Experimental — accuracy not yet measured
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
Thoreen, C. C., Kang, S. A., Chang, J. W., Liu, Q., Zhang, J., Gao, Y., Reichling, L. J., Sim, T., Sabatini, D. M., & Gray, N. S. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m900301200 · Cited by 1,803
Antitumor Activity and Mechanism of Action of the Cyclopenta[b]benzofuran, Silvestrol
Cencic, R., Carrier, M., Galicia-Vázquez, G., Bordeleau, M.-E., Sukarieh, R., Bourdeau, A., Brem, B., Teodoro, J. G., Greger, H., Tremblay, M. L., et al. (2009) · PLoS ONE · doi:10.1371/journal.pone.0005223 · Cited by 302
Self-citationmTORC1 promotes survival through translational control of Mcl-1
Mills, J. R., Hippo, Y., Robert, F., Chen, S. M. H., Malina, A., Lin, C.-J., Trojahn, U., Wendel, H.-G., Charest, A., Bronson, R. T., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0804821105 · Cited by 285 · cited 2×
“Eµ-Myc/Tsc2/ lym phomas are generated by crossing Eµ-Myc+/ mice to Tsc2+/ mice (Mills et al., 2008).”
BackgroundSelf-citation
Flagged first, then by citations
Research works printed but not linked: 33
- Adams, 1985, The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice, Nature., 318, 533, 10.1038/318533a0 · DOI
- Alizadeh, 2000, Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling, Nature., 403, 503, 10.1038/35000501 · DOI · Paper page
- Basso, 2005, Reverse engineering of regulatory networks in human B cells, Nat. Genet., 37, 382, 10.1038/ng1532 · DOI
- Bordeleau, 2008, Therapeutic suppression of translation initiation modulates chemosensitivity in a mouse lymphoma model, J. Clin. Invest., 118, 2651
- Chen, 2009, Pim kinase inhibitor, SGI-1776, induces apoptosis in chronic lymphocytic leukemia cells, Blood., 114, 4150, 10.1182/blood-2009-03-212852 · DOI
- Dancey, 2010, mTOR signaling and drug development in cancer, Nat Rev Clin Oncol., 7, 209, 10.1038/nrclinonc.2010.21 · DOI
- Dancey, 2009, Evaluating temsirolimus activity in multiple tumors: a review of clinical trials, Semin. Oncol., 36, S46, 10.1053/j.seminoncol.2009.10.010 · DOI
- Egle, 2004, VavP-Bcl2 transgenic mice develop follicular lymphoma preceded by germinal center hyperplasia, Blood., 103, 2276, 10.1182/blood-2003-07-2469 · DOI
- Feldman, 2009, Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2, PLoS Biol., 7, e38, 10.1371/journal.pbio.1000038 · DOI
- Fox, 2003, The serine/threonine kinase Pim-2 is a transcriptionally regulated apoptotic inhibitor, Genes Dev., 17, 1841, 10.1101/gad.1105003 · DOI
- Gómez-Abad, 2011, PIM inhibition as a rational therapeutic approach in diffuse large B-cell lymphoma, Ann. Oncol., 22, iv136
- Hammerman, 2005, Pim and Akt oncogenes are independent regulators of hematopoietic cell growth and survival, Blood., 105, 4477, 10.1182/blood-2004-09-3706 · DOI
- Hedvat, 2002, Application of tissue microarray technology to the study of non-Hodgkin’s and Hodgkin’s lymphoma, Hum. Pathol., 33, 968, 10.1053/hupa.2002.127438 · DOI
- Hess, 2009, Phase III study to evaluate temsirolimus compared with investigator’s choice therapy for the treatment of relapsed or refractory mantle cell lymphoma, J. Clin. Oncol., 27, 3822, 10.1200/JCO.2008.20.7977 · DOI
- Hoover, 1997, Pim-1 protein expression is regulated by its 5′-untranslated region and translation initiation factor elF-4E, Cell Growth Differ., 8, 1371
- Hsi, 2008, Ki67 and PIM1 expression predict outcome in mantle cell lymphoma treated with high dose therapy, stem cell transplantation and rituximab: a Cancer and Leukemia Group B 59909 correlative science study, Leuk. Lymphoma., 49, 2081, 10.1080/10428190802419640 · DOI
- Lenz, 2008, Stromal gene signatures in large-B-cell lymphomas, N. Engl. J. Med., 359, 2313, 10.1056/NEJMoa0802885 · DOI
- Mavrakis, 2008, Tumorigenic activity and therapeutic inhibition of Rheb GTPase, Genes Dev., 22, 2178, 10.1101/gad.1690808 · DOI
- Mavrakis, 2010, Genome-wide RNA-mediated interference screen identifies miR-19 targets in Notch-induced T-cell acute lymphoblastic leukaemia, Nat. Cell Biol., 12, 372, 10.1038/ncb2037 · DOI
- Morwick, 2010, Pim kinase inhibitors: a survey of the patent literature, Expert Opin Ther Pat., 20, 193, 10.1517/13543770903496442 · DOI
- Nawijn, 2011, For better or for worse: the role of Pim oncogenes in tumorigenesis, Nat. Rev. Cancer., 11, 23, 10.1038/nrc2986 · DOI
- O’Reilly, 2006, mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt, Cancer Res., 66, 1500, 10.1158/0008-5472.CAN-05-2925 · DOI · Paper page
- Poulsen, 2005, Microarray-based classification of diffuse large B-cell lymphoma, Eur. J. Haematol., 74, 453, 10.1111/j.1600-0609.2005.00429.x · DOI
- Rong, 2008, Control of eIF4E cellular localization by eIF4E-binding proteins, 4E-BPs, RNA., 14, 1318, 10.1261/rna.950608 · DOI
- Rosenwald, 2003, Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma, J. Exp. Med., 198, 851, 10.1084/jem.20031074 · DOI
- Sawyers, 2007, Cancer: mixing cocktails, Nature., 449, 993, 10.1038/449993a · DOI
- Smith, 2010, Temsirolimus has activity in non-mantle cell non-Hodgkin’s lymphoma subtypes: The University of Chicago phase II consortium, J. Clin. Oncol., 28, 4740, 10.1200/JCO.2010.29.2813 · DOI
- Sonenberg, 2009, Regulation of translation initiation in eukaryotes: mechanisms and biological targets, Cell., 136, 731, 10.1016/j.cell.2009.01.042 · DOI · Paper page
- Tee, 2003, Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb, Curr. Biol., 13, 1259, 10.1016/S0960-9822(03)00506-2 · DOI · Paper page
- Verbeek, 1991, Mice bearing the E mu-myc and E mu-pim-1 transgenes develop pre-B-cell leukemia prenatally, Mol. Cell. Biol., 11, 1176
- Wendel, 2004, Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy, Nature., 428, 332, 10.1038/nature02369 · DOI
- Wendel, 2007, Dissecting eIF4E action in tumorigenesis, Genes Dev., 21, 3232, 10.1101/gad.1604407 · DOI · Paper page
- Wright, 2003, A gene expression-based method to diagnose clinically distinct subgroups of diffuse large B cell lymphoma, Proc. Natl. Acad. Sci. USA., 100, 9991, 10.1073/pnas.1732008100 · DOI
Cited by
Sorted by citations
RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer
Wolfe, A. L., Singh, K., Zhong, Y., Drewe, P., Rajasekhar, V. K., Sanghvi, V. R., Mavrakis, K. J., Jiang, M., Roderick, J. E., Van der Meulen, J., et al. (2014) · Nature · doi:10.1038/nature13485 · Cited by 635
Self-citationFaber, A. C., Farago, A. F., Costa, C., Dastur, A., Gomez-Caraballo, M., Robbins, R., Wagner, B. L., Rideout, W. M., Jakubik, C. T., Ham, J., et al. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1411848112 · Cited by 127
Faber, A. C., Coffee, E. M., Costa, C., Dastur, A., Ebi, H., Hata, A. N., Yeo, A. T., Edelman, E. J., Song, Y., Tam, A. T., et al. (2014) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-0315 · Cited by 124
NRF2 Activation Confers Resistance to eIF4A Inhibitors in Cancer Therapy
Sanghvi, V. R., Mohan, P., Singh, K., Cao, L., Berishaj, M., Wolfe, A. L., Schatz, J. H., Lailler, N., de Stanchina, E., Viale, A., et al. (2021) · Cancers · doi:10.3390/cancers13040639 · Cited by 27
“more modestly against pancreatic cancer [21,34,35].”
Self-citation
Metadata
- Authors
- Schatz, J. H., Oricchio, E., Wolfe, A. L., Jiang, M., Linkov, I., Maragulia, J., Shi, W., Zhang, Z., Rajasekhar, V. K., Pagano, N. C., Porco, J. A., Teruya-Feldstein, J., Rosen, N., Zelenetz, A. D., Pelletier, J., & Wendel, H.-G.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Boston University (US)
- Department of Medicine 4 , 5 , and 6
- Institut du cancer Rosalind & Morris Goodman (CA)
- Corresponding author
- Wendel, Hans-Guido
- ORCID
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2011-08-22
- Volume
- 208
- Issue
- 9
- Pages
- 1799-1807
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC3171093
- OpenAlex
- W2102954277
- Cited by
- 119
- References
- 3
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 4 · 2023: 4 · 2022: 1 · 2021: 7 · 2020: 4 · 2019: 6 · 2018: 9 · 2017: 7 · 2016: 15 · 2015: 8 · 2014: 17 · 2013: 17 · 2012: 9
- FWCI
- 5.24
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- OpenBU (Boston University) (submittedVersion, cc-by-nc-sa)
- Funders
- Dana Foundation
- Lymphoma Research Foundation
- Leukemia Research Foundation
- American Society of Clinical Oncology
- Memorial Sloan-Kettering Cancer Center
- National Institutes of Health
- Canadian Cancer Society Research Institute
- National Cancer Institute (R01CA142798)
- National Institute of General Medical Sciences (R01GM073855)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Keywords
- cap-dependent translation, lymphoma, Akt kinase, PIM kinases, chemoresistance, rapamycin, mTORC1 inhibition, translation initiation, c-Myc, cyclin D1, Mcl-1, kinase inhibitor resistance, targeted therapy
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Animals, Antibiotics, Antineoplastic, Humans, Lymphoma, Proteins, Proto-Oncogene Proteins, RNA Caps, Transcription Factors, Protein Biosynthesis, Tumor Cells, Cultured, Signal Transduction, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Protein Serine-Threonine Kinases, Drug Resistance, Neoplasm, Sirolimus, Multiprotein Complexes, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-akt, Mice, Proto-Oncogene Proteins c-pim-1, TOR Serine-Threonine Kinases
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
