The effect of imiquimod on matrix metalloproteinases and tissue inhibitors of metalloproteinase in malignant melanoma cell invasion

Abstract

Imiquimod is an immune response modulator for treatment of superficial skin cancers and viral warts. Numerous reports have also been published regarding the use of imiquimod for treatment of melanoma in situ and metastatic melanoma. Cutaneous melanomas are notorious for their tendency to invade and metastasize. Essential steps in this process are degradation of basement membranes and remodeling of the extracellular matrix (ECM) by proteolytic enzymes, including matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitors of metalloproteinases (TIMPs).This study evaluated the anti-invasive effect of imiquimod in human malignant melanoma cell lines, SK-MEL-2 and SK-MEL-24, in vitro. And this study also investigated changes in expression of MMP-2, -9, and membrane type 1 matrix metalloproteinase (MT1-MMP), the key enzymes known to degrade surrounding ECM components during cancer invasion and metastasis, and their inhibitors, TIMP-1 and -2, under the influence of imiquimod. Imiquimod treatment resulted in decreased in vitro viability of melanoma cells in a concentration-dependent manner. And imiquimod also showed concentration-dependent suppression of invasion in both melanoma cell lines. Both melanoma cell lines showed a concentration-dependent decrease in MMP-2 and MT1-MMP protein levels and a concentration-dependent increase in TIMP-1 and -2 protein levels by imiquimod. However, expression of MMP-9 protein level increased in SK-MEL-2 but decreased in SK-MEL-24 according to the increase in imiquimod concentration. In real-time quantitative RT-PCR, imiquimod was shown to induce similar changes in expression of MMPs and TIMPs mRNA levels to protein levels. These results suggest that imiquimod may have an anti-invasive effect on human melanoma cells via regulation of MMPs and TIMPs.