Overexpression of Extracellular Matrix Metalloproteinase Inducer in Multidrug Resistant Cancer Cells1 1 US Public Health Service National Cancer Institute CA 66077 and CA 72720. Note: J-M. Yang and Z. Xu contributed equally to this study

• Published in: Molecular cancer research Vol. 1; no. 6; p. 420
• Main Authors: Jin-Ming Yang, Zude Xu, Hao Wu, Hongguang Zhu, Xiaohua Wu, William N. Hait
• Format: Journal Article
• Language: English
• Published: American Association for Cancer Research 01.04.2003
• Subjects: extracellular matrix metalloproteinase inducer; matrix metalloproteinase; mitogen-activated protein kinase; multidrug resistance; P-glycoprotein
• ISSN: 1541-7786; 1557-3125

Multidrug resistant (MDR) cancer cells overexpressing P-glycoprotein (P-gp) display variations in invasive and metastatic behavior. We previously reported that these properties of MDR cancer cell lines overexpressing P-gp could be altered by chemotherapeutic drugs or MDR modulators (R. S. Kerbel et al. , Cancer Surv., 7: 597–629, 1988). To attempt to clarify the mechanism(s) underlying these observations, we studied the expression of extracellular matrix metalloproteinase inducer (EMMPRIN), a glycoprotein enriched on the surface of tumor cells that can stimulate the production of matrix metalloproteinases (MMPs), in sensitive and MDR cancer cells. Using immunofluorescence staining and fluorescence-activated cell sorting analysis, we found that EMMPRIN expression was increased in MDR carcinoma cell lines, MCF-7/AdrR, KBV-1, and A2780Dx5, as compared to their parental counterparts. The MDR cell lines produced more matrix metalloproteinase-1 (MMP-1), matrix metalloproteinase-2 (MMP-2), and matrix metalloproteinase-9 (MMP-9), as determined by zymography, Western blot, and reverse transcription-PCR. Treatment of MDR cells with an anti-EMMPRIN antibody inhibited the activity of MMP-1, MMP-2, and MMP-9. In MDR cell line MCF-7/AdrR, an increased in vitro invasive ability was observed as compared with the sensitive line MCF-7, and EMMPRIN antibody could inhibit the in vitro invasion in drug-resistant cells. In addition, the expression and activity of MMP-1, MMP-2, and MMP-9 in MDR cells were decreased by treatment with U-0126, an inhibitor of mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/Erk). Our results suggest that during the development of MDR, the expression of EMMPRIN is responsible for the increased activity of MMP in MDR cell lines.