Thant A A, Nawa A, Kikkawa F, Ichigotani Y, Zhang Y, Sein T T, Amin A R, Hamaguchi M
Department of Molecular Pathogenesis, Nagoya University School of Medicine, Japan.
Clin Exp Metastasis. 2000;18(5):423-8. doi: 10.1023/a:1010921730952.
Cell adhesion to the extracellular matrix appears to trigger a cascade of intracellular signalings. We have previously shown that treatment of ovarian cancer cells, NOM1, with fibronectin (FN) stimulated matrix metalloproteinase (MMP)-9 secretion and thereby activated the invasiveness of cells via the FAK/Ras signaling pathway. By use of chemical inhibitors, we investigated the downstream effectors critical for FN-dependent secretion of MMP-9. Treatment of cells with MEK1 inhibitors, U0126 and PD98059, dramatically suppressed the secretion of MMP-9 activated by FN. Similarly, P1-3 kinase inhibitors, Wortmannin and LY294002, strongly suppressed the FN-dependent secretion of MMP-9 together with the inhibition of Akt activation. In contrast, a specific PKC inhibitor (GF109203X) showed no inhibitory effect on the FN-dependent MMP-9 secretion. Moreover, we found that both the MEK1 inhibitor and the P13-K inhibitor, but not the PKC inhibitor, strongly suppressed the invasiveness of NOM1 cells. Taken together, our results suggest that activation of dual signaling pathways, MEKI-MAPK and P13K-Akt, is required for the FN-dependent activation of MMP-9 secretion. Our results suggest the importance of these signaling molecules as a chemotherapeutic target for cancer.
细胞与细胞外基质的黏附似乎会引发一系列细胞内信号传导。我们之前已经表明，用纤连蛋白（FN）处理卵巢癌细胞NOM1会刺激基质金属蛋白酶（MMP）-9的分泌，从而通过FAK/Ras信号通路激活细胞的侵袭性。通过使用化学抑制剂，我们研究了对FN依赖的MMP-9分泌至关重要的下游效应器。用MEK1抑制剂U0126和PD98059处理细胞，可显著抑制FN激活的MMP-9分泌。同样，PI-3激酶抑制剂渥曼青霉素和LY294002在抑制Akt激活的同时，强烈抑制FN依赖的MMP-9分泌。相比之下，一种特异性PKC抑制剂（GF109203X）对FN依赖的MMP-9分泌没有抑制作用。此外，我们发现MEK1抑制剂和PI3-K抑制剂，而不是PKC抑制剂，强烈抑制NOM1细胞的侵袭性。综上所述，我们的结果表明，MEK1-MAPK和PI3K-Akt这两条双信号通路的激活是FN依赖的MMP-9分泌激活所必需的。我们的结果表明这些信号分子作为癌症化疗靶点的重要性。
