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Modulation of u-PA, MMPs and their inhibitors by a novel nutrient mixture in human glioblastoma cell lines

M.Waheed Roomi, Tatiana Kalinovsky, Aleksandra Niedzwiecki* and Matthias Rath
Dr. Rath Research Institute, Santa Clara, CA
International Journal of Oncology 2014; 45: 887-894

Brain tumors are highly aggressive tumors that are characterized by high levels of matrix metalloproteinase (MMP)-2 and -9 secretions that degrade the extracellular membrane (ECM) and basement membrane, allowing cancer cells to spread to distal organs. Proteases play a key role in tumor cell invasion and metastasis by digesting the basement membrane and ECM components. Strong clinical and experimental evidence demonstrates association of elevated levels of urokinase plasminogen activators (uPA) and MMPs with cancer progression, metastasis and shortened patient survival. MMP activities are regulated by specific tissue inhibitors of metalloproteinases (TIMPs). Our main objective was to study the effect of a nutrient mixture (NM) on activity of uPA, MMPs and TIMPs in various human gliomas.

Human glioblastoma (LN-18, T-98G and A-172) cell lines (ATCC) were cultured in their respective media and treated at confluence with NM at 0, 50, 100, 250, 500 and 1000 µg/ml. Analysis of uPA activity was carried out by fibrin zymography, MMPs by gelatinase zymography and TIMPs by reverse zymography. Glioblastoma cell lines LN-18 and T-98G expressed uPA, which was inhibited by NM in a dose-dependent manner. However, no bands corresponding to uPA were detected for cell line A-172. On gelatinase zymography, all three cell lines showed bands corresponding to MMP-2 and LN-18 and T-98G showed PMA (100 ng/ml) -induced MMP-9. NM inhibited their expression in a dose-dependent manner. Activity of TIMP-2 was up regulated by NM in all glioma cell lines in a dose–dependent manner. Analysis revealed a positive correlation between uPA and MMP-2 and a negative correlation between uPA /MMPs and TIMP-2. These findings suggest the therapeutic potential of NM in treatment of gliomas.

Key words: 
glioblastoma LN-18, T-98G and A-172, uPA, MMP-2 and MMP-9, TIMP-2, PMA, nutrient mixture