دورية أكاديمية
Therapeutic effect of imatinib in gastrointestinal stromal tumors: AKT signaling dependent and independent mechanisms.
| العنوان: | Therapeutic effect of imatinib in gastrointestinal stromal tumors: AKT signaling dependent and independent mechanisms. |
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| المؤلفون: | Tarn C; Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA., Skorobogatko YV, Taguchi T, Eisenberg B, von Mehren M, Godwin AK |
| المصدر: | Cancer research [Cancer Res] 2006 May 15; Vol. 66 (10), pp. 5477-86. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 2984705R Publication Model: Print Cited Medium: Print ISSN: 0008-5472 (Print) Linking ISSN: 00085472 NLM ISO Abbreviation: Cancer Res Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Baltimore, Md. : American Association for Cancer Research Original Publication: Chicago [etc.] |
| مواضيع طبية MeSH: | Gastrointestinal Stromal Tumors/*drug therapy , Gastrointestinal Stromal Tumors/*metabolism , Piperazines/*pharmacology , Proto-Oncogene Proteins c-akt/*metabolism , Pyrimidines/*pharmacology, Apoptosis/drug effects ; Benzamides ; Chromones/pharmacology ; Gastrointestinal Stromal Tumors/enzymology ; Gastrointestinal Stromal Tumors/pathology ; Glucose/pharmacokinetics ; Glucose Transporter Type 4/biosynthesis ; Glucose Transporter Type 4/metabolism ; Humans ; Imatinib Mesylate ; Morpholines/pharmacology ; Mutation ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphorylation/drug effects ; Proto-Oncogene Proteins c-kit/genetics ; Signal Transduction/drug effects ; Tumor Cells, Cultured |
| مستخلص: | Most gastrointestinal stromal tumors (GISTs) possess a gain-of-function mutation in c-KIT. Imatinib mesylate, a small-molecule inhibitor against several receptor tyrosine kinases, including KIT, platelet-derived growth factor receptor-alpha, and BCR-ABL, has therapeutic benefit for GISTs both via KIT and via unknown mechanisms. Clinical evidence suggests that a potential therapeutic benefit of imatinib might result from decreased glucose uptake as measured by positron emission tomography using 18-fluoro-2-deoxy-d-glucose. We sought to determine the mechanism of and correlation to altered metabolism and cell survival in response to imatinib. Glucose uptake, cell viability, and apoptosis in GIST cells were measured following imatinib treatment. Lentivirus constructs were used to stably express constitutively active AKT1 or AKT2 in GIST cells to study the role of AKT signaling in metabolism and cell survival. Immunoblots and immunofluorescent staining were used to determine the levels of plasma membrane-bound glucose transporter Glut4. We show that oncogenic activation of KIT maximizes glucose uptake in an AKT-dependent manner. Imatinib treatment markedly reduces glucose uptake via decreased levels of plasma membrane-bound Glut4 and induces apoptosis or growth arrest by inhibiting KIT activity. Importantly, expression of constitutively active AKT1 or AKT2 does not rescue cells from the imatinib-mediated apoptosis although glucose uptake was not blocked, suggesting that the potential therapeutic effect of imatinib is independent of AKT activity and glucose deprivation. Overall, these findings contribute to a clearer understanding of the molecular mechanisms involved in the therapeutic benefit of imatinib in GIST and suggest that a drug-mediated decrease in tumor metabolism observed clinically may not entirely reflect therapeutic efficacy of treatment. |
| معلومات مُعتمدة: | 3 U10 CA21661-27 United States CA NCI NIH HHS; CA106588-01 United States CA NCI NIH HHS; P50 CA83638 United States CA NCI NIH HHS |
| المشرفين على المادة: | 0 (Benzamides) 0 (Chromones) 0 (Glucose Transporter Type 4) 0 (Morpholines) 0 (Piperazines) 0 (Pyrimidines) 0 (SLC2A4 protein, human) 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one) 8A1O1M485B (Imatinib Mesylate) EC 2.7.1.- (Phosphatidylinositol 3-Kinases) EC 2.7.10.1 (Proto-Oncogene Proteins c-kit) EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) IY9XDZ35W2 (Glucose) |
| تواريخ الأحداث: | Date Created: 20060519 Date Completed: 20060718 Latest Revision: 20161128 |
| رمز التحديث: | 20240628 |
| DOI: | 10.1158/0008-5472.CAN-05-3906 |
| PMID: | 16707477 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 0008-5472 |
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| DOI: | 10.1158/0008-5472.CAN-05-3906 |