Overexpression of extracellular matrix metalloproteinase inducer in multidrug resistant Cancer cells

• Published in: Molecular cancer research 2003-04, Vol.1 (6), p.420-427
• Main Authors: YANG, Jin-Ming, ZUDE XU, HAO WU, HONGGUANG ZHU, XIAOHUA WU, HAIT, William N
• Format: Article
• Language: English
• Subjects: Antigens, CD; Antigens, Neoplasm; Basigin; Biological and medical sciences; Cell differentiation, maturation, development, hematopoiesis; Cell Division; Cell Line, Tumor; Cell physiology; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Fundamental and applied biological sciences. Psychology; Humans; Matrix Metalloproteinases - genetics; Matrix Metalloproteinases - metabolism; Membrane Glycoproteins - antagonists & inhibitors; Membrane Glycoproteins - metabolism; Molecular and cellular biology; Neoplasm Invasiveness
• 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.