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Nonsteroidal anti-inflammatory drugs suppress cancer stem cells via inhibiting PTGS2 (cyclooxygenase 2) and NOTCH/HES1 and activating PPARG in colorectal cancer

 Chang Mo Moon  ;  Ji-Hee Kwon  ;  Ji Suk Kim  ;  Sun-Hee Oh  ;  Kyoung Jin Lee  ;  Jae Jun Park  ;  Sung Pil Hong  ;  Jae Hee Cheon  ;  Tae Il Kim  ;  Won Ho Kim 
 INTERNATIONAL JOURNAL OF CANCER, Vol.134(3) : 519-529, 2014 
Journal Title
Issue Date
Animals ; Anti-Inflammatory Agents, Non-Steroidal/pharmacology* ; Basic Helix-Loop-Helix Transcription Factors/antagonists & inhibitors* ; Cell Line, Tumor ; Colorectal Neoplasms/enzymology ; Colorectal Neoplasms/metabolism ; Colorectal Neoplasms/pathology* ; Cyclooxygenase 2/drug effects* ; Homeodomain Proteins/antagonists & inhibitors* ; Humans ; Male ; Mice ; Mice, Inbred BALB C ; Neoplastic Stem Cells/drug effects* ; Neoplastic Stem Cells/enzymology ; Neoplastic Stem Cells/metabolism ; PPAR gamma/agonists* ; Receptors, Notch/antagonists & inhibitors* ; Transcription Factor HES-1 ; Xenograft Model Antitumor Assays
NOTCH ; PPARG ; colonic cancer stem cell ; cyclooxygenase 2 ; nonsteroidal anti-inflammatory drugs
Cancer stem cells (CSCs) play a pivotal role in cancer relapse or metastasis. We investigated the CSC-suppressing effect of nonsteroidal anti-inflammatory drugs (NSAIDs) and the relevant mechanisms in colorectal cancer. We measured the effect of NSAIDs on CSC populations in Caco-2 or SW620 cells using colosphere formation and flow cytometric analysis of PROM1 (CD133)+CD44+ cells after indomethacin treatment with/without prostaglandin E2 (PGE2) or peroxisome proliferator-activated receptor γ (PPARG) antagonist, and examined the effect of indomethacin on transcriptional activity and protein expression of NOTCH/HES1 and PPARG. These effects of indomethacin were also evaluated in a xenograft mouse model. NSAIDs (indomethacin, sulindac and aspirin), celecoxib, γ-secretase inhibitor and PPARG agonist significantly decreased the number of colospheres formation compared to controls. In Caco-2 and SW620 cells, compared to controls, PROM1 (CD133)+CD44+ cells were significantly decreased by indomethacin treatment, and increased by 5-fluorouracil (5-FU) treatment. This 5-FU-induced increase of PROM1 (CD133)+CD44+ cells was significantly attenuated by combination with indomethacin. This CSC-inhibitory effect of indomethacin was reversed by addition of PGE2 and PPARG antagonist. Indomethacin significantly decreased CBFRE and increased PPRE transcriptional activity and their relative protein expressions. In xenograft mouse experiments using 5-FU-resistant SW620 cells, the 5-FU treatment combined with indomethacin significantly reduced tumor growth, compared to 5-FU alone. In addition, treatment of indomethacin alone or combination of 5-FU and indomethacin decreased the expressions of PROM1 (CD133), CD44, PTGS2 (cyclooxygenase 2) and HES1, and increased PPARG expression. NSAIDs could selectively reduce the colon CSCs and suppress 5-FU-induced increase of CSCs via inhibiting PTGS2 (cyclooxygenase 2) and NOTCH/HES1, and activating PPARG.
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1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kwon. Ji Hee(권지희)
Kim, Won Ho(김원호) ORCID logo https://orcid.org/0000-0002-5682-9972
Kim, Ji Suk(김지숙)
Kim, Tae Il(김태일) ORCID logo https://orcid.org/0000-0003-4807-890X
Moon, Chang Mo(문창모)
Park, Jae Jun(박재준)
Lee, Kyoung Jin(이경진)
Cheon, Jae Hee(천재희) ORCID logo https://orcid.org/0000-0002-2282-8904
Hong, Sung Pil(홍성필)
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