PMID- 20803081
OWN - NLM
STAT- MEDLINE
DCOM- 20110609
LR  - 20151119
IS  - 1534-4681 (Electronic)
IS  - 1068-9265 (Linking)
VI  - 18
IP  - 2
DP  - 2011 Feb
TI  - mTOR signaling is involved in indomethacin and nimesulide suppression of 
      colorectal cancer cell growth via a COX-2 independent pathway.
PG  - 580-8
LID - 10.1245/s10434-010-1268-9 [doi]
AB  - BACKGROUND: Inhibition of mammalian target of rapamycin (mTOR) represents an 
      attractive target for anticancer therapy, but its role in suppression of 
      colorectal cancer (CRC) cell growth by cyclooxygenase-2 (COX-2) inhibitors is 
      unclear. Here, we analyzed the effect of indomethacin (Indo, a nonselective COX-2 
      inhibitor) and nimesulide (Nim, a selective COX-2 inhibitor) on mTOR signaling in 
      CRC cells in vitro and in vivo to determine the dependence of this effect on 
      COX-2. METHODS: Human CRC cell lines with varying COX-2 expression levels were 
      treated with Indo and Nim. Western blot test was performed to detect mTOR-related 
      components (mTOR, p70s6 K, and 4EBP1), and cell viability, cell cycle, and 
      apoptosis were assessed. HCT116 and SW1116 cells were injected into athymic nude 
      mice to establish a CRC xenograft model. After treatment with Nim, tumor volume, 
      mTOR signaling, and apoptosis were evaluated in this model. HT29 and SW1116 cells 
      were also treated with Nim after transfection with COX-2-specific small 
      interfering RNA (siRNA) to assess dependence of COX-2 on mTOR signaling under 
      drug treatment. RESULTS: Both Indo and Nim reduced mTOR signaling activity in CRC 
      cells that differ in their COX-2 expression in vitro and in vivo. Additionally, 
      Indo and Nim could reduce the mTOR signaling activity after COX-2 silencing in 
      CRC cells. CONCLUSIONS: mTOR signaling is involved in Indo- and Nim-mediated 
      suppression of CRC growth via a COX-2 independent pathway. This study unveils a 
      novel mechanism through which COX-2 inhibitors exerts their anticancer effects 
      and further emphasizes targeting mTOR signaling in anticancer therapy.
FAU - Zhang, Yan-Jie
AU  - Zhang YJ
AD  - Department of Digestion, Shanghai Jiaotong University, School of Medicine, 
      Shanghai, China. zhangyanjie2007@126.com
FAU - Bao, Yu-Jie
AU  - Bao YJ
FAU - Dai, Qiang
AU  - Dai Q
FAU - Yang, Wen-Yan
AU  - Yang WY
FAU - Cheng, Peng
AU  - Cheng P
FAU - Zhu, Li-Ming
AU  - Zhu LM
FAU - Wang, Bi-Jun
AU  - Wang BJ
FAU - Jiang, Fo-Hu
AU  - Jiang FH
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20100828
PL  - United States
TA  - Ann Surg Oncol
JT  - Annals of surgical oncology
JID - 9420840
RN  - 0 (Cyclooxygenase 2 Inhibitors)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Sulfonamides)
RN  - EC 1.14.99.1 (Cyclooxygenase 2)
RN  - V4TKW1454M (nimesulide)
RN  - XXE1CET956 (Indomethacin)
SB  - IM
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Blotting, Western
MH  - Cell Cycle/drug effects
MH  - Cell Proliferation/*drug effects
MH  - Colorectal Neoplasms/drug therapy/*metabolism/pathology
MH  - Cyclooxygenase 2/*chemistry/metabolism
MH  - Cyclooxygenase 2 Inhibitors/*pharmacology
MH  - Humans
MH  - Indomethacin/*pharmacology
MH  - Male
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Nude
MH  - RNA, Small Interfering/genetics
MH  - Signal Transduction/*drug effects
MH  - Sulfonamides/*pharmacology
MH  - Tumor Cells, Cultured
EDAT- 2010/08/31 06:00
MHDA- 2011/06/10 06:00
CRDT- 2010/08/31 06:00
PHST- 2010/04/14 00:00 [received]
PHST- 2010/08/31 06:00 [entrez]
PHST- 2010/08/31 06:00 [pubmed]
PHST- 2011/06/10 06:00 [medline]
AID - 10.1245/s10434-010-1268-9 [doi]
PST - ppublish
SO  - Ann Surg Oncol. 2011 Feb;18(2):580-8. doi: 10.1245/s10434-010-1268-9. Epub 2010 
      Aug 28.