The Regulation of Matrix Metalloproteinase Expression and the Role of Discoidin Domain Receptor 1/2 Signalling in Zoledronate-treated PC3 Cells

Discoidin Domain Receptors (DDR1/DDR2) are tyrosine kinase receptors which are activated by collagen. DDR signalling regulates cell migration, proliferation, apoptosis and matrix metalloproteinase (MMP) production. MMPs degrade extracellular matrix (ECM) and play essential role in tumor growth, invasion and metastasis. Nitrogen-containing bisphosphonates (N-BPs) which strongly inhibit osteoclastic activity are commonly used for osteoporosis treatment. They also have MMP inhibitory effect. In this study, we aimed to investigate the effects of zoledronate in PC3 cells and the possible role of DDR signalling and downstream pathways in these inhibitory effects. We studied messenger RNA (mRNA) and protein expressions of MMP-2,-9,-8, DDR1/DDR2 type I procollagen (TIP) and mRNA levels of PCA-1, MMP-13 and DDR-initiated signalling pathway players including K-Ras oncogene, ERK1, JNK1, p38, AKT-1 and BCLX in PC3 cells in the presence or absence of zoledronate (10-100 mu M) for 2-3 days. Zoledronate (100 mu M) down-regulated DDR1/DDR2, TIP mRNAs but did not change MMP-13 (collagenase-3) mRNA. However, zoledronate up-regulated MMP-8 (collagenase-2) mRNA. Zoledronate also inhibited mRNA expressions of K-Ras, ERK1, AKT-1, BCLX and PCA-1; but did not change JNK1, p38 mRNA levels. Zoledronate (100 mu M) supressed DDR1/DDR2, TIP expressions; and gelatinase (MMP-2/MMP-9) expressions/activities. Conversely, zoledronate up-regulated MMP-8 expression in PC3 cells. Zoledronate down-regulates MMP-2/-9 expressions in PC3 prostate cancer cells. DDR1/DDR2 signalling and DDR-initiated downstream Ras/Raf/ERK and PI3K/AKT pathways may at least partially responsible for MMP inhibitory effect of zoledronate.