Regulation of motility and protease expression in PKC-mediated induction of MCF-7 breast cancer cell invasiveness
Regulation of motility and protease expression in PKC-mediated induction of MCF-7 breast cancer cell invasiveness
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DOI：
10.1006/excr.1998.4336
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发表时间：
1999-02-25
影响因子：
3.7
通讯作者：
Dickson, RB
中科院分区：
文献类型：
--
作者：
Johnson, MD;Torri, JA;Dickson, RB
我们研究了蛋白激酶C（PKC）在控制乳腺癌细胞侵袭性的多个途径中的潜在核心作用。为此，我们评估了改变PKC活性的药物调节侵袭性差的人乳腺癌细胞系MCF-7的行为的能力。用12-O-十四酰基佛波醇-13-乙酸酯（TPA）处理产生了对这些细胞的侵袭性的显著诱导（18倍），这是用PKC抑制剂苔藓抑素-1同时处理能够阻断的效果。为了表征可能对这些效果负责的细胞特性的改变，我们测量了这两种药剂对被认为对侵袭性重要的许多过程的影响。首先检查细胞的运动性;用TPA处理显著增加（20倍），并且再次，苔藓抑素-1抑制这种刺激。我们接下来检测了MMP-1、3、9、10和11（基质金属蛋白酶）的表达，所有这些都已被证明在其他系统中是PKC应答的。我们发现MMP-9的表达和分泌增加了至少100倍，尽管所有分泌的酶都是潜伏形式。最后，尿激酶纤溶酶原激活物（UPA）及其受体（UPAR）的表达诱导TPA治疗后，分别为8和7倍。总之，我们已经表明，PKC活性的刺激显着增加MCF-7细胞的侵袭性，这种行为的变化与一组协调的生化和细胞的变化，这可能有助于这一过程。这些数据突出了PKC抑制剂如苔藓抑素-1作为抗侵袭和/或抗转移剂的可能效用。苔藓抑素-I目前作为抗癌剂处于早期临床试验中。(C)北京：科学出版社.
We investigated a potentially central role of protein kinase C (PKC) in controlling multiple pathways in breast cancer cell invasiveness. To do this we evaluated the ability of pharmacologic agents that alter PKC activity to regulate the behavior of the poorly invasive human breast cancer cell line MCF-7. Treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA) produced a dramatic induction of the invasiveness of these cells (18-fold), an effect that concurrent treatment with the PKC inhibitor Bryostatin-l was able to block, To characterize alterations in the cellular properties that might be responsible for these effects we measured the impact of these two agents on a number of processes thought to be important for invasiveness. The motility of the cells was first examined; it was markedly increased by treatment with TPA (20-fold) and again, Bryostatin-l inhibited this stimulation. We next examined the expression of MMP-1, 3, 9, 10, and 11 (matrix metalloproteinases), all of which have been shown to be PKC responsive in other systems. We found that the expression and secretion of MMP-9 were increased by at least 100-fold, though all of the enzyme secreted was in the latent form. Finally, the expression of both urokinase plasminogen activator (UPA) and its receptor (UPAR) were induced after TPA treatment by 8- and 7-fold, respectively. In conclusion, we have shown that stimulation of PKC activity markedly increases the invasiveness of MCF-7 cells, and that this change in behavior is correlated with a coordinated set of biochemical and cellular changes which are likely to contribute to this process. These data highlight the possible utility of PKC inhibitors such as Bryostatin-l as anti-invasive and/or antimetastatic agents. Bryostatin-l is currently in early clinical trials as an anticancer agent. (C) 1999 Academic Press.