Distinct mechanisms mediate the initial and sustained phases of cell migration in epidermal growth factor receptor-overexpressing cells.
Distinct mechanisms mediate the initial and sustained phases of cell migration in epidermal growth factor receptor-overexpressing cells.
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发表时间：
2003-09
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通讯作者：
Joseph S Kruger;K. Reddy
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作者：
Joseph S Kruger;K. Reddy
在许多人类癌症中，表皮生长因子受体(EGFR)水平的升高预示着侵袭和转移的增加。在本研究中，我们发现了两条不同的途径来调节EGFR过表达的侵袭性细胞(如乳腺癌细胞)的迁移：丝裂原活化蛋白激酶(MAPK或ERK1和2)途径在细胞迁移的早期阶段起主要作用；蛋白激酶C增量异构体(PKC-Delta)在细胞持续迁移的后期阶段起重要作用。用MAPK(MEK)抑制剂PD98059抑制MAPK活性可阻断细胞迁移的早期阶段(长达4h)；然而，细胞在4h后恢复到促进细胞迁移的状态。而用rotlerin或显性阴性的PKC-Delta表达抑制PKC-Delta活性可在4h至12h阻止持续的细胞迁移，MAPK和PKC抑制剂的组合完全阻断转化生长因子-α(TGF-α)诱导的EGFR高表达乳腺癌细胞的细胞迁移。然而，抑制MAPK活性完全阻止了低表达EGFR的非侵袭性乳腺癌细胞如MCF-7细胞的迁移。在MCF-7细胞(EGFR/MCF-7细胞)中强制过表达EGFR导致了MDA468细胞的迁移模式，即MAPK通路在细胞迁移的早期阶段起主要作用，而PKC-Delta在细胞持续迁移的后期阶段起主要作用。以上结果表明，过度表达EGFR的侵袭细胞能够通过激活PKC-Delta信号通路来补偿MAPK介导的信号的丢失，从而促进细胞的迁移，在侵袭和转移中发挥重要作用。此外，数据表明，抑制MAPK和PKC-Delta信号通路应该可以消除EGFR过表达的人乳腺癌细胞中的细胞迁移和侵袭。
Elevated levels of epidermal growth factor receptor (EGFR) are predictive of increased invasion and metastasis in many human cancers. In the present study, we have shown that two distinct pathways regulate cell migration in EGFR-overexpressing invasive cells such as MDA 468 breast cancer cells: mitogen-activated protein kinase (MAPK or ERK 1 and 2) pathways play a major role in early stages to cell migration; and protein kinase C delta isoforms (PKC-delta) play a significant role in later stages of sustained cell migration. Inhibition of MAPK activity with MAP kinase kinase (MEK) inhibitor PD98059 blocks early stages of cell migration (up to 4 h); however, cells revert back to enhanced cell migration after 4 h. While inhibition of PKC-delta activity with rottlerin or dominant-negative PKC-delta expression blocks sustained cell migration after 4 h and up to 12 h, the combination of MAPK and PKC inhibitors completely blocked transforming growth factor alpha (TGF-alpha)-induced cell migration in EGFR-overexpressing breast cancer cells. However, inhibition of MAPK activity completely blocked cell migration in low EGFR-expressing non-invasive breast cancer cells such as MCF-7 cells. Forced overexpression of EGFR in MCF-7 cells (EGFR/MCF-7 cells) resulted in cell migration patterns seen in MDA 468 cells, that is, MAPK pathways play a major role in early stages to cell migration, and PKC-delta plays a major role in later stages of sustained cell migration. The above data demonstrate that EGFR-overexpressing invasive cells have the ability to compensate the loss of MAPK-mediated signaling through activation of PKC-delta signaling for cell migration, which plays a major role in invasion and metastasis. In addition, data suggest that inhibition of MAPK and PKC-delta signaling pathways should abrogate cell migration and invasion in EGFR-overexpressing human breast cancer cells.