Show simple item record Balakumaran, BS Porrello, A Hsu, DS Glover, W Foye, A Leung, JY Sullivan, BA Hahn, WC Loda, M Febbo, PG
dc.coverage.spatial United States 2011-06-21T17:27:30Z 2009-10-01
dc.identifier 0008-5472.CAN-09-0910
dc.identifier.citation Cancer Res, 2009, 69 (19), pp. 7803 - 7810
dc.description.abstract Loss of PTEN and activation of phosphoinositide 3-kinase are commonly observed in advanced prostate cancer. Inhibition of mammalian target of rapamycin (mTOR), a downstream target of phosphoinositide 3-kinase signaling, results in cell cycle arrest and apoptosis in multiple in vitro and in vivo models of prostate cancer. However, single-agent use of mTOR inhibition has limited clinical success, and the identification of molecular events mitigating tumor response to mTOR inhibition remains a critical question. Here, using genetically engineered human prostate epithelial cells (PrEC), we show that MYC, a frequent target of genetic gain in prostate cancers, abrogates sensitivity to rapamycin by decreasing rapamycin-induced cytostasis and autophagy. Analysis of MYC and the mTOR pathway in human prostate tumors and PrEC showed selective increased expression of eukaryotic initiation factor 4E-binding protein 1 (4EBP1) with gain in MYC copy number or forced MYC expression, respectively. We have also found that MYC binds to regulatory regions of the 4EBP1 gene. Suppression of 4EBP1 expression resulted in resensitization of MYC-expressing PrEC to rapamycin and increased autophagy. Taken together, our findings suggest that MYC expression abrogates sensitivity to rapamycin through increased expression of 4EBP1 and reduced autophagy.
dc.format.extent 7803 - 7810
dc.language eng
dc.language.iso en_US en_US
dc.relation.ispartof Cancer Res
dc.relation.isversionof 10.1158/0008-5472.CAN-09-0910
dc.subject Antibiotics, Antineoplastic
dc.subject Autophagy
dc.subject Cell Line, Tumor
dc.subject Drug Resistance, Neoplasm
dc.subject E-Box Elements
dc.subject Eukaryotic Initiation Factor-4E
dc.subject Genes, myc
dc.subject Humans
dc.subject Male
dc.subject Prostatic Neoplasms
dc.subject Protein Kinases
dc.subject Proto-Oncogene Proteins c-myc
dc.subject Sirolimus
dc.subject TOR Serine-Threonine Kinases
dc.subject Tunicamycin
dc.title MYC activity mitigates response to rapamycin in prostate cancer through eukaryotic initiation factor 4E-binding protein 1-mediated inhibition of autophagy.
dc.title.alternative en_US
dc.type Journal Article
dc.description.version Version of Record en_US 2010-2-16 en_US
duke.description.endpage 282 en_US
duke.description.issue 2 en_US
duke.description.startpage 281 en_US
duke.description.volume 6 en_US
dc.relation.journal Autophagy en_US
pubs.issue 19
pubs.organisational-group /Duke
pubs.organisational-group /Duke/School of Medicine
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments/Molecular Genetics and Microbiology
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Medicine
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Medicine/Medicine, Medical Oncology
pubs.organisational-group /Duke/School of Medicine/Institutes and Centers
pubs.organisational-group /Duke/School of Medicine/Institutes and Centers/Duke Cancer Institute
pubs.publication-status Published
pubs.volume 69
dc.identifier.eissn 1538-7445

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