title: Nonsteroidal anti-inflammatory drugs suppress cancer stem cells via inhibiting PTGS2 (cyclooxygenase 2) and NOTCH/HES1 and activating PPARG in colorectal cancer.
abstract: 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.
authors.affiliation: Department of Internal Medicine, Graduate School, Yonsei University College of Medicine, Seoul, Republic of Korea; Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Chang Mo
authors.initials: CM
authors.lastname: Moon
authors.forename: Ji-Hee
authors.initials: JH
authors.lastname: Kwon
authors.forename: Ji Suk
authors.initials: JS
authors.lastname: Kim
authors.forename: Sun-Hee
authors.initials: SH
authors.lastname: Oh
authors.forename: Kyoung
authors.initials: K
authors.lastname: Jin Lee
authors.forename: Jae Jun
authors.initials: JJ
authors.lastname: Park
authors.forename: Sung
authors.initials: S
authors.lastname: Pil Hong
authors.forename: Jae Hee
authors.initials: JH
authors.lastname: Cheon
authors.forename: Tae Il
authors.initials: TI
authors.lastname: Kim
authors.forename: Won Ho
authors.initials: WH
authors.lastname: Kim
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D051546:Cyclooxygenase 2 / Q000187:drug effects*; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists*; D051880:Receptors, Notch / Q000037:antagonists & inhibitors*; D000072056:Transcription Factor HES-1; D023041:Xenograft Model Antitumor Assays
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D051792:Basic Helix-Loop-Helix Proteins; D051546:Cyclooxygenase 2; D018398:Homeodomain Proteins; D047495:PPAR gamma; D051880:Receptors, Notch; D000072056:Transcription Factor HES-1; C078493:HES1 protein, human; C496540:PTGS2 protein, human
keywords: NOTCH; PPARG; colonic cancer stem cell; cyclooxygenase 2; nonsteroidal anti-inflammatory drugs