| Rapamycin partially mimics the anticancer effects of calorie restriction in a murine model of pancreatic cancer. | |
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MedLine Citation:
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PMID: 21593197 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Etiologic factors for pancreatic cancer, the 4th deadliest malignant neoplasm in the United States, include obesity and abnormal glucose metabolism. Calorie restriction (CR) and rapamycin each affect energy metabolism and cell survival pathways via inhibition of mammalian target of rapamycin (mTOR) signaling. By using a Panc02 murine pancreatic cancer cell transplant model in 45 male C57BL/6 mice, we tested the hypothesis that rapamycin mimics the effects of CR on pancreatic tumor growth. A chronic regimen of CR, relative to an ad libitum-fed control diet, produced global metabolic effects such as reduced body weight (20.6 ± 1.6 g vs. 29.3 ± 2.3 g; P < 0.0001), improved glucose responsiveness, and decreased circulating levels of insulin-like growth factor (IGF)-1 (126 ± 8 ng/mL vs. 199 ± 11 ng/mL; P = 0.0006) and leptin (1.14 ± 0.2 ng/mL vs. 5.05 ± 1.2 ng/mL; P = 0.01). In contrast, rapamycin treatment (2.5 mg/kg intraperitoneal every other day, initiated in mice following 20 weeks of ad libitum control diet consumption), relative to control diet, produced no significant change in body weight, IGF-1 or leptin levels, but decreased glucose responsiveness. Pancreatic tumor volume was significantly reduced in the CR group (221 ± 107 mm(3); P < 0.001) and, to a lesser extent, the rapamycin group (374 ± 206 mm(3); P = 0.04) relative to controls (550 ± 147 mm(3)), and this differential inhibition correlated with expression of the proliferation marker Ki-67. Both CR and rapamycin decreased phosphorylation of mTOR, p70/S6K, and S6 ribosomal protein, but only CR decreased phosphorylation of Akt, GSK-3β, extracellular signal regulated kinase/mitogen-activated protein kinase, and STAT3(TYR705). These findings suggest that rapamycin partially mimics the anticancer effects of CR on tumor growth in a murine model of pancreatic cancer. |
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Authors:
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Laura M Lashinger; Lauren M Malone; Graham W Brown; Elizabeth A Daniels; Jason A Goldberg; Glen Otto; Susan M Fischer; Stephen D Hursting |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2011-05-18 |
Journal Detail:
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Title: Cancer prevention research (Philadelphia, Pa.) Volume: 4 ISSN: 1940-6215 ISO Abbreviation: Cancer Prev Res (Phila) Publication Date: 2011 Jul |
Date Detail:
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Created Date: 2011-07-07 Completed Date: 2011-11-15 Revised Date: 2012-02-23 |
Medline Journal Info:
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Nlm Unique ID: 101479409 Medline TA: Cancer Prev Res (Phila) Country: United States |
Other Details:
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Languages: eng Pagination: 1041-51 Citation Subset: IM |
Affiliation:
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Department of Molecular Carcinogenesis, University of Texas M.D. Anderson Cancer Center, Smithville, Texas, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antibiotics, Antineoplastic / therapeutic use* Blotting, Western Body Weight / drug effects Caloric Restriction* Carcinoma, Pancreatic Ductal / metabolism, pathology, prevention & control* Combined Modality Therapy Disease Models, Animal* Glucose / metabolism Glucose Tolerance Test Glycogen Synthase Kinase 3 / metabolism Immunoenzyme Techniques Insulin-Like Growth Factor I / metabolism Male Mice Mice, Inbred C57BL Mitogen-Activated Protein Kinases / metabolism Pancreatic Neoplasms / metabolism, pathology, prevention & control* Phosphorylation / drug effects Proto-Oncogene Proteins c-akt / metabolism Ribosomal Protein S6 Kinases, 70-kDa / metabolism STAT3 Transcription Factor / metabolism Sirolimus / therapeutic use* TOR Serine-Threonine Kinases / metabolism Tumor Cells, Cultured |
| Grant Support | |
ID/Acronym/Agency:
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R01 CA135386/CA/NCI NIH HHS; R01 CA135386-01A1/CA/NCI NIH HHS; R01 CA135386-04/CA/NCI NIH HHS; R25T CA57730/CA/NCI NIH HHS; T32 CA135386/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antibiotics, Antineoplastic; 0/STAT3 Transcription Factor; 0/Stat3 protein, mouse; 50-99-7/Glucose; 53123-88-9/Sirolimus; 67763-96-6/Insulin-Like Growth Factor I; EC 2.7.1.1/TOR Serine-Threonine Kinases; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 2.7.11.1/Ribosomal Protein S6 Kinases, 70-kDa; EC 2.7.11.1/glycogen synthase kinase 3 beta; EC 2.7.11.24/Mitogen-Activated Protein Kinases; EC 2.7.11.26/Glycogen Synthase Kinase 3 |
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