PMID- 19773438
OWN - NLM
STAT- MEDLINE
DCOM- 20091203
LR  - 20240312
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 69
IP  - 19
DP  - 2009 Oct 1
TI  - MYC activity mitigates response to rapamycin in prostate cancer through 
      eukaryotic initiation factor 4E-binding protein 1-mediated inhibition of 
      autophagy.
PG  - 7803-10
LID - 10.1158/0008-5472.CAN-09-0910 [doi]
AB  - 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.
FAU - Balakumaran, Bala S
AU  - Balakumaran BS
AD  - Duke Institute for Genome Sciences and Policy and Duke Comprehensive Cancer 
      Center, Duke University, NC 27710, USA.
FAU - Porrello, Alessandro
AU  - Porrello A
FAU - Hsu, David S
AU  - Hsu DS
FAU - Glover, Wayne
AU  - Glover W
FAU - Foye, Adam
AU  - Foye A
FAU - Leung, Janet Y
AU  - Leung JY
FAU - Sullivan, Beth A
AU  - Sullivan BA
FAU - Hahn, William C
AU  - Hahn WC
FAU - Loda, Massimo
AU  - Loda M
FAU - Febbo, Phillip G
AU  - Febbo PG
LA  - eng
GR  - R01 CA123175/CA/NCI NIH HHS/United States
GR  - R01 CA123175-01A2/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20090922
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Antibiotics, Antineoplastic)
RN  - 0 (Eukaryotic Initiation Factor-4E)
RN  - 0 (Proto-Oncogene Proteins c-myc)
RN  - 11089-65-9 (Tunicamycin)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Antibiotics, Antineoplastic/*pharmacology
MH  - Autophagy/drug effects/physiology
MH  - Cell Line, Tumor
MH  - Drug Resistance, Neoplasm
MH  - E-Box Elements
MH  - Eukaryotic Initiation Factor-4E/biosynthesis/genetics/*metabolism
MH  - Genes, myc
MH  - Humans
MH  - Male
MH  - Prostatic Neoplasms/*drug therapy/genetics/metabolism/pathology
MH  - Protein Kinases/biosynthesis/genetics/metabolism
MH  - Proto-Oncogene Proteins c-myc/biosynthesis/genetics/*metabolism
MH  - Sirolimus/*pharmacology
MH  - TOR Serine-Threonine Kinases
MH  - Tunicamycin/pharmacology
PMC - PMC2756305
MID - NIHMS140254
COIS- Conflicts of Interest: None
EDAT- 2009/09/24 06:00
MHDA- 2009/12/16 06:00
PMCR- 2010/10/01
CRDT- 2009/09/24 06:00
PHST- 2009/09/24 06:00 [entrez]
PHST- 2009/09/24 06:00 [pubmed]
PHST- 2009/12/16 06:00 [medline]
PHST- 2010/10/01 00:00 [pmc-release]
AID - 0008-5472.CAN-09-0910 [pii]
AID - 10.1158/0008-5472.CAN-09-0910 [doi]
PST - ppublish
SO  - Cancer Res. 2009 Oct 1;69(19):7803-10. doi: 10.1158/0008-5472.CAN-09-0910. Epub 
      2009 Sep 22.