Mixed lineage kinase 3 is required for matrix metalloproteinase expression and invasion in ovarian cancer cells

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• 作者：Yu Zhan ; Widian F. Abi Saab ; Nidhi Modi ; Am ; a M. Stewart ; Jinsong Liu ; Deborah N. Chadee
• 关键词：MLK3 ; MMP ; Invasion ; Ovarian cancer ; MAPK ; AP-1
• 刊名：Experimental Cell Research
• 出版年：2012
• 出版时间：15 August, 2012
• 年：2012
• 卷：318
• 期：14
• 页码：1641-1648
• 全文大小：757 K

文摘

Mixed lineage kinase 3 (MLK3) is a mitogen-activated protein kinase kinase kinase (MAP3K) that activates MAPK signaling pathways and regulates cellular responses such as proliferation, migration and apoptosis. Here we report high levels of total and phospho-MLK3 in ovarian cancer cell lines in comparison to immortalized nontumorigenic ovarian epithelial cell lines. Using small interfering RNA (siRNA)-mediated gene silencing, we determined that MLK3 is required for the invasion of SKOV3 and HEY1B ovarian cancer cells. Furthermore, mlk3 silencing substantially reduced matrix metalloproteinase (MMP)-1, -2, -9 and -12 gene expression and MMP-2 and -9 activities in SKOV3 and HEY1B ovarian cancer cells. MMP-1, -2, -9 and-12 expression, and MLK3-induced activation of MMP-2 and MMP-9 requires both extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) activities. In addition, inhibition of activator protein-1 (AP-1) reduced MMP-1, MMP-9 and MMP-12 gene expression. Collectively, these findings establish MLK3 as an important regulator of MMP expression and invasion in ovarian cancer cells.