MYC activity mitigates response to rapamycin in prostate cancer through eukaryotic initiation factor 4E-binding protein 1-mediated inhibition of autophagy.

dc.contributor.author

Balakumaran, Bala S

dc.contributor.author

Porrello, Alessandro

dc.contributor.author

Hsu, David S

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Glover, Wayne

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Foye, Adam

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Leung, Janet Y

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Sullivan, Beth A

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Hahn, William C

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Loda, Massimo

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Febbo, Phillip G

dc.coverage.spatial

United States

dc.date.accessioned

2011-06-21T17:27:30Z

dc.date.issued

2009-10-01

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.description.version

Version of Record

dc.identifier

https://www.ncbi.nlm.nih.gov/pubmed/19773438

dc.identifier

0008-5472.CAN-09-0910

dc.identifier.eissn

1538-7445

dc.identifier.uri

https://hdl.handle.net/10161/4170

dc.language

eng

dc.language.iso

en_US

dc.publisher

American Association for Cancer Research (AACR)

dc.relation.ispartof

Cancer Res

dc.relation.isversionof

10.1158/0008-5472.CAN-09-0910

dc.relation.journal

Autophagy

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Antibiotics, Antineoplastic

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Autophagy

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Cell Line, Tumor

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Drug Resistance, Neoplasm

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E-Box Elements

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Eukaryotic Initiation Factor-4E

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Genes, myc

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Humans

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Male

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Prostatic Neoplasms

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Protein Kinases

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Proto-Oncogene Proteins c-myc

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Sirolimus

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TOR Serine-Threonine Kinases

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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
dc.type

Journal article

duke.contributor.orcid

Sullivan, Beth A|0000-0001-5216-4603

duke.date.pubdate

2010-2-16

duke.description.issue

2

duke.description.volume

6

pubs.author-url

https://www.ncbi.nlm.nih.gov/pubmed/19773438

pubs.begin-page

7803

pubs.end-page

7810

pubs.issue

19

pubs.organisational-group

Basic Science Departments

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Clinical Science Departments

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Duke

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Duke Cancer Institute

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Institutes and Centers

pubs.organisational-group

Medicine

pubs.organisational-group

Medicine, Medical Oncology

pubs.organisational-group

Molecular Genetics and Microbiology

pubs.organisational-group

School of Medicine

pubs.publication-status

Published

pubs.volume

69

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