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

Balakumaran, Bala S

Porrello, Alessandro

Hsu, David S

Glover, Wayne

Foye, Adam

Leung, Janet Y

Sullivan, Beth A

Hahn, William C

Loda, Massimo

Febbo, Phillip G

United States

2011-06-21T17:27:30Z

2009-10-01

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.

Version of Record

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

0008-5472.CAN-09-0910

1538-7445

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

eng

en_US

American Association for Cancer Research (AACR)

Cancer Res

10.1158/0008-5472.CAN-09-0910

Autophagy

Antibiotics, Antineoplastic

Autophagy

Cell Line, Tumor

Drug Resistance, Neoplasm

E-Box Elements

Eukaryotic Initiation Factor-4E

Genes, myc

Humans

Male

Prostatic Neoplasms

Protein Kinases

Proto-Oncogene Proteins c-myc

Sirolimus

TOR Serine-Threonine Kinases

Tunicamycin

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

Journal article

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

2010-2-16

2

6

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

7803

7810

19

Basic Science Departments

Clinical Science Departments

Duke

Duke Cancer Institute

Institutes and Centers

Medicine

Medicine, Medical Oncology

Molecular Genetics and Microbiology

School of Medicine

Published

69