Yao M, Lam E C, Kelly C R, Zhou W, Wolfe M M
Section of Gastroenterology, Boston University School of Medicine and Boston Medical Center, 650 Albany Street, Boston, MA 02118, USA.
Br J Cancer. 2004 Feb 9;90(3):712-9. doi: 10.1038/sj.bjc.6601489.
Nonsteroidal anti-inflammatory drugs (NSAIDs) have been reported to reduce the risk and mortality of colorectal cancer (CRC) by inhibiting the activity of cyclooxygenase (COX). The present studies were directed to determine whether selective COX-2 inhibition reduces CRC tumour cell proliferation and invasion/migration, and the possible cellular and molecular mechanisms involved. The MC-26 cells are a highly invasive mouse CRC cell line expressing COX-2 protein. NS-398 (100 microM), a highly selective COX-2 inhibitor, decreased cell proliferation by approximately 35% of control, as determined using [(3)H]-thymidine incorporation. This reduction in cell proliferation was associated with decreased expression of cyclin D1 and proliferating cell nuclear antigen (PCNA). Furthermore, NS-398 inhibited cell invasion/migration through Matrigel extracellular matrix components at 24 h by approximately 60%. The addition of exogenous prostaglandin E(2) partially attenuated the inhibition of cell invasion by 10 microM NS-398, but failed to reverse the effect of 100 microM NS-398. Matrix metalloproteinases-2 (MMP-2) and -9 (MMP-9) are two enzymes that facilitate cell invasion/migration by degrading the extracellular matrix. In the presence of 100 microM NS-398, Western blot hybridisation analysis and zymography demonstrated that both MMP-2 and MMP-9 protein levels and enzyme activity were decreased by approximately 25-30%. In separate studies, NS-398 also inhibited tumour growth in vivo and retarded the formation of liver metastasis. The results of these studies indicate that the expression and activity of COX-2 appear to be associated with both the proliferative and invasive properties of CRC. Cyclooxygenase-2 inhibition suppresses tumour cell growth and invasion/migration, and retards liver metastasis in a mouse colon cancer model, via multiple cellular and molecular mechanisms.
据报道，非甾体抗炎药（NSAIDs）通过抑制环氧化酶（COX）的活性来降低结直肠癌（CRC）的风险和死亡率。目前的研究旨在确定选择性COX-2抑制是否能降低CRC肿瘤细胞的增殖以及侵袭/迁移能力，以及其中可能涉及的细胞和分子机制。MC-26细胞是一种高度侵袭性的小鼠CRC细胞系，表达COX-2蛋白。使用[³H] - 胸腺嘧啶核苷掺入法测定，高度选择性的COX-2抑制剂NS-398（100微摩尔）使细胞增殖降低了约35%，与对照组相比。细胞增殖的这种降低与细胞周期蛋白D1和增殖细胞核抗原（PCNA）表达的降低有关。此外，NS-398在24小时时抑制细胞通过基质胶细胞外基质成分的侵袭/迁移约60%。添加外源性前列腺素E₂部分减弱了10微摩尔NS-398对细胞侵袭的抑制作用，但未能逆转100微摩尔NS-398的作用。基质金属蛋白酶-2（MMP-2）和-9（MMP-9）是两种通过降解细胞外基质促进细胞侵袭/迁移的酶。在存在100微摩尔NS-398的情况下，蛋白质印迹杂交分析和酶谱分析表明，MMP-2和MMP-9的蛋白水平和酶活性均降低了约25 - 30%。在单独的研究中，NS-398还在体内抑制肿瘤生长并延缓肝转移的形成。这些研究结果表明，COX-2的表达和活性似乎与CRC的增殖和侵袭特性均相关。在小鼠结肠癌模型中，抑制环氧化酶-2通过多种细胞和分子机制抑制肿瘤细胞生长和侵袭/迁移，并延缓肝转移。
