Suthiphongchai Tuangporn, Phimsen Suchada, Sakulkhu Usawadee, Tohtong Rutaiwan
Department of Biochemistry, Mahidol University, Rama 6 Road, Bangkok 10400, Thailand.
Oncol Rep. 2006 Jun;15(6):1605-10.
Up-regulation of extracellular-regulated kinases 1/2 (ERK1/2) has been implicated in tumor progression and metastasis in many types of cancer. We have previously shown that ERK1/2 is necessary for invasiveness of Dunning rat prostatic adenocarcinoma cell lines in which levels of activated ERK1/2 correlate with the metastatic potential. Here, we further examined the biological effects of elevated ERK1/2 in the highly metastatic Dunning cell line, MLL, in which the abilities to invade and metastasize are enhanced relative to its progenitor strain. Inhibition of ERK1/2 activation by the MEK1 inhibitor, PD98059, dose-dependently reduced MLL cell invasiveness and motility with similar IC50 values. On the other hand, the abilities of MLL cells to adhere to the extracellular matrix, phosphorylate myosin regulatory light chain and secrete matrix-degrading enzymes, matrix metalloproteinase (MMP)-2 and urokinase plasminogen activator (uPA) were marginally, if at all, affected by PD98059 treatment. These data indicated that the inhibitory effect of PD98059 on the invasiveness of MLL cells was primarily due to the suppression of cell motility, and the up-regulation of ERK1/2 is, at least in part, responsible for the enhanced cellular motility and invasiveness of the MLL cells.
细胞外调节激酶1/2（ERK1/2）的上调与多种癌症的肿瘤进展和转移有关。我们之前已经表明，ERK1/2对于邓宁大鼠前列腺腺癌细胞系的侵袭性是必需的，其中活化的ERK1/2水平与转移潜能相关。在此，我们进一步研究了在高转移性邓宁细胞系MLL中ERK1/2升高的生物学效应，相对于其亲代菌株，MLL细胞的侵袭和转移能力增强。MEK1抑制剂PD98059对ERK1/2激活的抑制作用剂量依赖性地降低了MLL细胞的侵袭性和运动性，IC50值相似。另一方面，PD98059处理对MLL细胞黏附于细胞外基质、磷酸化肌球蛋白调节轻链以及分泌基质降解酶基质金属蛋白酶（MMP）-2和尿激酶型纤溶酶原激活剂（uPA）的能力即使有影响也微乎其微。这些数据表明，PD98059对MLL细胞侵袭性的抑制作用主要是由于细胞运动性的抑制，并且ERK1/2的上调至少部分地导致了MLL细胞增强的细胞运动性和侵袭性。
