PMID- 20395440
OWN - NLM
STAT- MEDLINE
DCOM- 20101004
LR  - 20211203
IS  - 1525-2191 (Electronic)
IS  - 0002-9440 (Print)
IS  - 0002-9440 (Linking)
VI  - 176
IP  - 6
DP  - 2010 Jun
TI  - Mammalian target of rapamycin (mTOR) regulates cellular proliferation and tumor 
      growth in urothelial carcinoma.
PG  - 3062-72
LID - 10.2353/ajpath.2010.090872 [doi]
AB  - Mammalian target of rapamycin (mTOR) signaling has been associated with 
      aggressive tumor growth in many cancer models, although its role in urothelial 
      carcinoma (UCC) has not been extensively explored. Expression of phosphorylated 
      mTOR (P-mTOR) and a downstream target, ribosomal S6 protein (P-S6), was 
      identified in 74% (90/121) and 55% (66/121) of muscle-invasive UCCs, 
      respectively. P-mTOR intensity and %positive cells were associated with reduced 
      disease-specific survival (P = 0.04, P = 0.08, respectively). Moreover, P-mTOR 
      intensity corresponded to increased pathological stage (P < 0.01), and mTOR 
      activity was associated with cell migration in vitro. In addition, mTOR 
      inhibition via rapamycin administration reduced cell proliferation in UCC cell 
      lines RT4, T24, J82, and UMUC3 in a dose-dependent manner to 6% of control levels 
      and was significant at 1 nmol/L in J82, T24, and RT4 cells (P < 0.01, P < 0.01, P 
      = 0.03, respectively) and at 10 nmol/L in UMUC3 cells (P = 0.03). Reduced 
      proliferation corresponded with reduced P-S6 levels by Western blot, and effects 
      were ablated by pretreatment of cells with mTOR-specific siRNA. No effects of 
      rapamycin on apoptosis were identified by TUNEL labeling or PARP cleavage. 
      Administration of rapamycin to T24-xenografted mice resulted in a 55% reduction 
      in tumor volume (P = 0.03) and a 40% reduction in proliferation (P < 0.01) 
      compared with vehicle-injected mice. These findings indicate that mTOR pathway 
      activation frequently occurs in UCC and that mTOR inhibition may be a potential 
      means to reduce UCC growth.
FAU - Hansel, Donna E
AU  - Hansel DE
AD  - Department of Anatomic Pathology, Cleveland Clinic, Cleveland, Ohio, USA. 
      hanseld@ccf.org
FAU - Platt, Eric
AU  - Platt E
FAU - Orloff, Mohammed
AU  - Orloff M
FAU - Harwalker, Jyoti
AU  - Harwalker J
FAU - Sethu, Swathi
AU  - Sethu S
FAU - Hicks, Jessica L
AU  - Hicks JL
FAU - De Marzo, Angelo
AU  - De Marzo A
FAU - Steinle, Roxanne E
AU  - Steinle RE
FAU - Hsi, Eric D
AU  - Hsi ED
FAU - Theodorescu, Dan
AU  - Theodorescu D
FAU - Ching, Christina B
AU  - Ching CB
FAU - Eng, Charis
AU  - Eng C
LA  - eng
GR  - KL2 TR000440/TR/NCATS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20100415
PL  - United States
TA  - Am J Pathol
JT  - The American journal of pathology
JID - 0370502
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Animals
MH  - *Carcinoma, Transitional Cell/metabolism/pathology
MH  - Cell Line, Tumor/drug effects
MH  - *Cell Proliferation
MH  - Female
MH  - Humans
MH  - Intracellular Signaling Peptides and Proteins/genetics/*metabolism
MH  - Male
MH  - Mice
MH  - Mice, Nude
MH  - Middle Aged
MH  - Neoplasm Transplantation
MH  - Protein Serine-Threonine Kinases/genetics/*metabolism
MH  - Ribosomal Protein S6 Kinases, 70-kDa/genetics/metabolism
MH  - Signal Transduction/physiology
MH  - Sirolimus/pharmacology
MH  - Survival Rate
MH  - TOR Serine-Threonine Kinases
MH  - Transplantation, Heterologous
MH  - *Urinary Bladder Neoplasms/metabolism/pathology
PMC - PMC2877865
EDAT- 2010/04/17 06:00
MHDA- 2010/10/05 06:00
PMCR- 2011/06/01
CRDT- 2010/04/17 06:00
PHST- 2010/04/17 06:00 [entrez]
PHST- 2010/04/17 06:00 [pubmed]
PHST- 2010/10/05 06:00 [medline]
PHST- 2011/06/01 00:00 [pmc-release]
AID - S0002-9440(10)60825-5 [pii]
AID - 10.2353/ajpath.2010.090872 [doi]
PST - ppublish
SO  - Am J Pathol. 2010 Jun;176(6):3062-72. doi: 10.2353/ajpath.2010.090872. Epub 2010 
      Apr 15.