Increased Expression of Matrix Metalloproteinases Mediates Thromboxane A2-Induced Invasion in Lung Cancer Cells

Xiuling      Li; Hsin-Hsiung      Tai

doi:10.2174/156800912801784884

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.

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