Mixed lineage kinase 3 is required for matrix metalloproteinase expression and invasion in ovarian cancer cells.
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.
Department of Biological Sciences, The University of Toledo, Toledo, OH 43606, USA.
Yu
Y
Zhan
Widian F
WF
Abi Saab
Nidhi
N
Modi
Amanda M
AM
Stewart
Jinsong
J
Liu
Deborah N
DN
Chadee
D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D020782:Matrix Metalloproteinases / Q000235:genetics* / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D060888:Real-Time Polymerase Chain Reaction; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014407:Tumor Cells, Cultured; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11
D020930:MAP Kinase Kinase Kinases; D020782:Matrix Metalloproteinases; D018808:Transcription Factor AP-1; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11