Urokinase Plasminogen Activator/Urokinase-specific Surface Receptor Expression and Matrix Invasion by Breast Cancer Cells Requires Constitutive p38α Mitogen-activated Protein Kinase Activity

Shuang Huang,Liguo New,Zhixing Pan,Jiahuai Han,Glen R Nemerow

doi:10.1074/jbc.275.16.12266

Shuang Huang, Liguo New + Show 3 more

Open Access

https://doi.org/10.1074/jbc.275.16.12266

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Abstract

Overexpression of urokinase plasminogen activator (uPA) and its receptor (uPAR) has been well documented in a wide variety of tumor cells. In breast cancer, expression of uPA/uPAR is essential for tumor cell invasion and metastasis. However, the mechanism responsible for uPA/uPAR expression in cancer cells remains unclear. In the studies reported here, we show that endogenous p38 MAPK activity correlates well with breast carcinoma cell invasiveness. Treatment of highly invasive BT549 cells with a specific p38 MAPK inhibitor SB203580 diminished both uPA/uPAR mRNA and protein expression and abrogated the ability of these cells to invade matrigel, suggesting that p38 MAPK signaling pathway is involved in the regulation of uPA/uPAR expression and breast cancer cell invasion. We also demonstrated that SB203580-induced reduction in uPA/uPAR mRNA expression resulted from the de- stabilization of uPA and uPAR mRNA. Finally, by selectively inhibiting p38alpha or p38beta MAPK isoforms, we demonstrate that p38alpha, rather than p38beta, MAPK activity is essential for uPA/uPAR expression. These studies suggest that p38alpha MAPK signaling pathway is important for the maintenance of breast cancer invasive phenotype by promoting the stabilities of uPA and uPAR mRNA.

Highlights

In multicellular organisms, invasion plays a pivotal role in diverse physiological and pathological processes such as tissue remodeling associated with embryonic development [1], inflammation [2, 3], angiogenesis [4], wound healing [5], and tumor metastasis (6 –9)
Treatment of SB203580 reduced the half-life to approximately 3 and 2 h, respectively, for urokinase plasminogene activator (uPA) and urokinase-specific cell surface receptor (uPAR) mRNA (Fig. 6). These results suggest that signaling processes initiated by p38 mitogen-activated protein kinases (MAPKs) pathway alter the stability of uPA and uPAR mRNA. p38 MAPK Activity Is Not Required for uPA Transgene mRNA Expression—The 3Ј-untranslated region (3Ј-UTR) of uPA mRNA has been reported to influence the stability of uPA mRNA in cultured cells and transgenic mice (44 – 46)
Several recent studies have demonstrated that expression of several metalloproteinases including MMP-9 and metalloproteinase inducer-stimulated collagenase-1 (MMP-1) induced by extracellular stimuli is mediated by p38 MAPK signaling pathway

Summary

Introduction

Invasion plays a pivotal role in diverse physiological and pathological processes such as tissue remodeling associated with embryonic development [1], inflammation [2, 3], angiogenesis [4], wound healing [5], and tumor metastasis (6 –9). We provide substantial evidence that p38␣ MAPK pathway signals for the stability of uPA and uPAR mRNA and thereby may enhance breast cancer cell invasiveness. Endogenous p38 MAPK Activity Is Associated with Breast Cancer Cell in Vitro Invasiveness—The p38 MAPK signaling pathway has been shown to mediate the expression of several metalloproteinase induced by various extracellular stimuli (28 –31, 39).

Results

Conclusion