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.
Int J Cancer. 2014 Feb 1;134(3):519-29. doi: 10.1002/ijc.28381. Epub 2013 Aug 7.
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.
癌症干细胞 (CSC) 在癌症复发或转移中起关键作用。我们研究了非甾体抗炎药 (NSAIDs) 对结直肠癌细胞中 CSC 的抑制作用及其相关机制。我们通过 Colosphere 形成和经吲哚美辛处理后 PROM1（CD133）（+）CD44（+）细胞的流式细胞术分析，测量 NSAIDs 对 Caco-2 或 SW620 细胞中的 CSC 群体的影响，并用前列腺素 E2 (PGE2) 或过氧化物酶体增殖物激活受体 γ (PPARG) 拮抗剂处理吲哚美辛，并检测吲哚美辛对 NOTCH/HES1 和 PPARG 的转录活性和蛋白表达的影响。我们还在异种移植小鼠模型中评估了吲哚美辛的这些作用。与对照组相比，NSAIDs（吲哚美辛、舒林酸和阿司匹林）、塞来昔布、γ-分泌酶抑制剂和 PPARG 激动剂显著减少了 Colosphere 形成的数量。在 Caco-2 和 SW620 细胞中，与对照组相比，吲哚美辛处理后 PROM1（CD133）（+）CD44（+）细胞明显减少，而 5-氟尿嘧啶（5-FU）处理后则增加。5-FU 诱导的 PROM1（CD133）（+）CD44（+）细胞增加被与吲哚美辛联合治疗显著减弱。吲哚美辛的这种 CSC 抑制作用可通过添加 PGE2 和 PPARG 拮抗剂逆转。吲哚美辛显著降低 CBFRE，并增加 PPRE 转录活性及其相对蛋白表达。在使用 5-FU 耐药的 SW620 细胞的异种移植小鼠实验中，与单独使用 5-FU 相比，5-FU 联合吲哚美辛治疗显著减少了肿瘤生长。此外，单独使用吲哚美辛或联合使用 5-FU 和吲哚美辛治疗可降低 PROM1（CD133）、CD44、PTGS2（环氧化酶 2）和 HES1 的表达，并增加 PPARG 的表达。NSAIDs 可以通过抑制 PTGS2（环氧化酶 2）和 NOTCH/HES1 并激活 PPARG，选择性地减少结肠 CSC，并抑制 5-FU 诱导的 CSC 增加。
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