Title:Increased Expression of Matrix Metalloproteinases Mediates Thromboxane A2-Induced Invasion in Lung Cancer Cells
VOLUME: 12 ISSUE: 6
Author(s):Xiuling Li and Hsin-Hsiung Tai
Affiliation:Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 431 BPC, 789 S. Limestone Street, Lexington, KY 40536-0596, USA.
Keywords:Invasion, matrix metalloproteinase, metastasis, signal transduction, thromboxane A2 receptor
, activator protein-1, CCAAT/enhancer-binding protein , extracellular matrix, extracellular signal-regulated kinase, heparin-binding epidermal growth factor, mitogen-activated protein kinase, phosphoinositide-3-kinase, small interfering RNA, thromboxane synthase
Abstract:Thromboxane A2 receptor (TP) has been shown to play an important role in multiple aspects of cancer
development including regulation of tumor growth, survival and metastasis. Here we report that TP mediates cancer cell
invasion by inducing expression of matrix metalloproteinases (MMPs). TP agonist, I-BOP, significantly elevated MMP-1,
MMP-3, MMP-9 and MMP-10 mRNA levels in A549 human lung adenocarcinoma cells overexpressing TPα or TPβ. The
secretion of MMP-1 and MMP-9 in conditioned media was determined using Western blot analysis and zymographic
assay. Signaling pathways of I-BOP-induced MMP-1 expression were examined in further detail as a model system for
MMPs induction. Signaling molecules involved in I-BOP-induced MMP-1 expression were identified by using specific
inhibitors including small interfering (si)-RNAs of signaling molecules and promoter reporter assay. The results indicate
that I-BOP-induced MMP-1 expression is mediated by protein kinase C (PKC), extracellular signal-regulated kinase
(ERK)-activator protein-1(AP-1) and ERK-CCAAT/enhancer-binding protein β (C/EBPβ) pathways. I-BOP-induced
cellular invasiveness of A549 cells expressing TPα or TPβ was determined by invasion assay. GM6001, a general
inhibitor of MMPs, decreased basal and I-BOP-induced cell invasion. Knockdown of MMP-1 and MMP-9 by their
respective siRNA partially reduced I-BOP-stimulated cell invasion suggesting that other MMPs induced by I-BOP were
also involved. Our studies establish the relationship between TP and MMPs in cancer cell invasion and suggest that the
thromboxane A2 (TXA2)-TP signaling is a potential therapeutic target for cancer invasion and metastasis.
