PMID- 22187071
OWN - NLM
STAT- MEDLINE
DCOM- 20130114
LR  - 20211203
IS  - 1468-3288 (Electronic)
IS  - 0017-5749 (Linking)
VI  - 61
IP  - 12
DP  - 2012 Dec
TI  - 5-Aminosalicylic acid inhibits cell cycle progression in a phospholipase D 
      dependent manner in colorectal cancer.
PG  - 1708-15
LID - 10.1136/gutjnl-2011-301626 [doi]
AB  - BACKGROUND: 5-Aminosalicylic acid (5-ASA) may protect against the development of 
      inflammation-associated colorectal cancer. In vitro data suggest that, in 
      colorectal cancer cells, 5-ASA induces cell cycle arrest, but the molecular 
      mechanism leading to this arrest remains to be determined. AIM: To dissect the 
      signal transduction events that lead to 5-ASA mediated inhibition of 
      proliferation of colorectal cancer cells, focusing on mammalian target of 
      rapamycin (mTOR), a regulator of cell cycle progression. METHODS: The influence 
      of 5-ASA on mTOR signalling was examined in a panel of colorectal cancer cell 
      lines. The effects of 5-ASA on the pathways that control mTOR activity were 
      studied in detail in two different colorectal cancer cell lines, using western 
      blot, siRNA, a phospholipase D (PLD) activity assay, proliferation assays and 
      cell cycle analysis. The phosphorylation status of mTOR and its downstream 
      target, ribosomal protein S6, was studied in colorectal cancers before and after 
      topical 5-ASA treatment. RESULTS: Treatment of colorectal cancer with 5-ASA 
      inhibited mTOR signalling in vitro and in vivo. 5-ASA had no effect on any of the 
      pathways that regulate the activity of the tuberous sclerosis complex in 
      colorectal cancer cells. Both proliferation and mTOR activity depended on PLD, an 
      enzyme that generates phosphatidic acid (PA). 5-ASA treatment inhibited PLD 
      activity and proliferation; these effects could be rescued with exogenous PA. 
      CONCLUSION: 5-ASA interferes with proliferation of colorectal cancer cells via 
      inhibition of PLD-dependent generation of PA and loss of mTOR signalling.
FAU - Baan, Bart
AU  - Baan B
AD  - Tytgat Institute for Liver & Intestinal Research, Academic Medical Center, 
      Amsterdam, The Netherlands.
FAU - Dihal, Ashwin A
AU  - Dihal AA
FAU - Hoff, Eva
AU  - Hoff E
FAU - Bos, Carina L
AU  - Bos CL
FAU - Voorneveld, Philip W
AU  - Voorneveld PW
FAU - Koelink, Pim J
AU  - Koelink PJ
FAU - Wildenberg, Manon E
AU  - Wildenberg ME
FAU - Muncan, Vanesa
AU  - Muncan V
FAU - Heijmans, Jarom
AU  - Heijmans J
FAU - Verspaget, Hein W
AU  - Verspaget HW
FAU - Richel, Dick J
AU  - Richel DJ
FAU - Hardwick, James C H
AU  - Hardwick JC
FAU - Hommes, Daniel W
AU  - Hommes DW
FAU - Peppelenbosch, Maikel P
AU  - Peppelenbosch MP
FAU - van den Brink, Gijs R
AU  - van den Brink GR
LA  - eng
PT  - Evaluation Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20111220
PL  - England
TA  - Gut
JT  - Gut
JID - 2985108R
RN  - 0 (Anti-Inflammatory Agents, Non-Steroidal)
RN  - 0 (Biomarkers, Tumor)
RN  - 4Q81I59GXC (Mesalamine)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.1.4.4 (Phospholipase D)
SB  - IM
MH  - Anti-Inflammatory Agents, Non-Steroidal/*pharmacology/therapeutic use
MH  - Biomarkers, Tumor/metabolism
MH  - Blotting, Western
MH  - Cell Cycle/*drug effects
MH  - Cell Line, Tumor
MH  - Cell Proliferation/*drug effects
MH  - Colorectal Neoplasms/*drug therapy/metabolism
MH  - Humans
MH  - Mesalamine/*pharmacology/therapeutic use
MH  - Phospholipase D/*metabolism
MH  - Signal Transduction/*drug effects
MH  - TOR Serine-Threonine Kinases/metabolism
EDAT- 2011/12/22 06:00
MHDA- 2013/01/15 06:00
CRDT- 2011/12/22 06:00
PHST- 2011/12/22 06:00 [entrez]
PHST- 2011/12/22 06:00 [pubmed]
PHST- 2013/01/15 06:00 [medline]
AID - gutjnl-2011-301626 [pii]
AID - 10.1136/gutjnl-2011-301626 [doi]
PST - ppublish
SO  - Gut. 2012 Dec;61(12):1708-15. doi: 10.1136/gutjnl-2011-301626. Epub 2011 Dec 20.