دورية أكاديمية
أعرض في EDS

Response to mTOR inhibition: activity of eIF4E predicts sensitivity in cell lines and acquired changes in eIF4E regulation in breast cancer.

التفاصيل البيبلوغرافية
العنوان: Response to mTOR inhibition: activity of eIF4E predicts sensitivity in cell lines and acquired changes in eIF4E regulation in breast cancer.
المؤلفون: Satheesha S; Leeds Institute of Molecular Medicine, St, James's University Hospital, Leeds University, UK., Cookson VJ, Coleman LJ, Ingram N, Madhok B, Hanby AM, Suleman CA, Sabine VS, Macaskill EJ, Bartlett JM, Dixon JM, McElwaine JN, Hughes TA
المصدر: Molecular cancer [Mol Cancer] 2011 Feb 14; Vol. 10, pp. 19. Date of Electronic Publication: 2011 Feb 14.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: BioMed Central Country of Publication: England NLM ID: 101147698 Publication Model: Electronic Cited Medium: Internet ISSN: 1476-4598 (Electronic) Linking ISSN: 14764598 NLM ISO Abbreviation: Mol Cancer Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [London] : BioMed Central, c2002-
مواضيع طبية MeSH: Breast Neoplasms/*metabolism , Eukaryotic Initiation Factor-4E/*metabolism , TOR Serine-Threonine Kinases/*antagonists & inhibitors, 5' Untranslated Regions/genetics ; Adaptor Proteins, Signal Transducing/metabolism ; Breast Neoplasms/genetics ; Breast Neoplasms/pathology ; Breast Neoplasms/surgery ; Cell Cycle Proteins ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Drug Screening Assays, Antitumor ; Eukaryotic Initiation Factor-4E/genetics ; Everolimus ; Female ; Gene Expression Regulation, Neoplastic/drug effects ; Genes, Reporter ; Humans ; Phosphoproteins/metabolism ; Phosphorylation/drug effects ; Preoperative Care ; Protein Biosynthesis/drug effects ; Sirolimus/analogs & derivatives ; Sirolimus/pharmacology ; TOR Serine-Threonine Kinases/metabolism ; Tissue Culture Techniques
مستخلص: Background: Inhibitors of the kinase mTOR, such as rapamycin and everolimus, have been used as cancer therapeutics with limited success since some tumours are resistant. Efforts to establish predictive markers to allow selection of patients with tumours likely to respond have centred on determining phosphorylation states of mTOR or its targets 4E-BP1 and S6K in cancer cells. In an alternative approach we estimated eIF4E activity, a key effector of mTOR function, and tested the hypothesis that eIF4E activity predicts sensitivity to mTOR inhibition in cell lines and in breast tumours.
Results: We found a greater than three fold difference in sensitivity of representative colon, lung and breast cell lines to rapamycin. Using an assay to quantify influences of eIF4E on the translational efficiency specified by structured 5'UTRs, we showed that this estimate of eIF4E activity was a significant predictor of rapamycin sensitivity, with higher eIF4E activities indicative of enhanced sensitivity. Surprisingly, non-transformed cell lines were not less sensitive to rapamycin and did not have lower eIF4E activities than cancer lines, suggesting the mTOR/4E-BP1/eIF4E axis is deregulated in these non-transformed cells. In the context of clinical breast cancers, we estimated eIF4E activity by analysing expression of eIF4E and its functional regulators within tumour cells and combining these scores to reflect inhibitory and activating influences on eIF4E. Estimates of eIF4E activity in cancer biopsies taken at diagnosis did not predict sensitivity to 11-14 days of pre-operative everolimus treatment, as assessed by change in tumour cell proliferation from diagnosis to surgical excision. However, higher pre-treatment eIF4E activity was significantly associated with dramatic post-treatment changes in expression of eIF4E and 4E-binding proteins, suggesting that eIF4E is further deregulated in these tumours in response to mTOR inhibition.
Conclusions: Estimates of eIF4E activity predict sensitivity to mTOR inhibition in cell lines but breast tumours with high estimated eIF4E activity gain changes in eIF4E regulation in order to enhance resistance.
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المشرفين على المادة: 0 (5' Untranslated Regions)
0 (Adaptor Proteins, Signal Transducing)
0 (Cell Cycle Proteins)
0 (EIF4EBP1 protein, human)
0 (Eukaryotic Initiation Factor-4E)
0 (Phosphoproteins)
9HW64Q8G6G (Everolimus)
EC 2.7.1.1 (MTOR protein, human)
EC 2.7.11.1 (TOR Serine-Threonine Kinases)
W36ZG6FT64 (Sirolimus)
تواريخ الأحداث: Date Created: 20110216 Date Completed: 20110613 Latest Revision: 20211203
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC3055230
DOI: 10.1186/1476-4598-10-19
PMID: 21320304
قاعدة البيانات: MEDLINE
الوصف
تدمد:1476-4598
DOI:10.1186/1476-4598-10-19