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The Effect of Imiquimod on Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases in Malignant Melanoma Cell Invasion

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Background: A number of reports have been publishedregarding the use of imiquimod for the treatment of melanomain situ and metastatic melanoma. Essential steps inthe process of melanoma invasion and metastasis includedegradation of basement membranes and remodeling of theextracellular matrix by proteolytic enzymes, includingmatrix metalloproteinases (MMPs) and tissue inhibitors ofmetalloproteinases (TIMPs). Objective: To evaluate the antiinvasiveeffect of imiquimod in human malignant melanomacell lines, SK-MEL-2 and SK-MEL-24, in vitro, and to investigateimiquimod-induced changes in the expression ofMMPs and TIMPs. Methods: Invasiveness of melanoma celllines following imiquimod treatment was evaluated byinvasion assays. In order to investigate the mechanism of theanti-invasive effect of imiquimod, mRNA and protein levelsof MMP-2, -9, membrane type 1 (MT1)-MMP, TIMP-1, and -2were assessed by real-time reverse transcription-polymerasechain reaction, gelatin zymography, and western blotting. Results: Imiquimod treatment decreased in vitro viability ofmelanoma cells in a concentration-dependent manner. Imiquimodalso elicited a concentration-dependent suppressionof invasion in both melanoma cell lines. A concentration-dependent decrease in MMP-2 and MT1-MMPprotein levels and a concentration-dependent increase inTIMP-1 and -2 protein levels by imiquimod was observed inboth melanoma cell lines. However, expression of MMP-9protein was increased in SK-MEL-2 but decreased inSK-MEL-24 with increasing imiquimod concentrations. Imiquimod elicited alterations in MMPs and TIMPs mRNAlevels that parallel the observed changes in protein levels. Conclusion: Imiquimod may elicit an anti-invasive effect onhuman melanoma cells by regulating MMPs and TIMPs.

Abstract

Background: A number of reports have been publishedregarding the use of imiquimod for the treatment of melanomain situ and metastatic melanoma. Essential steps inthe process of melanoma invasion and metastasis includedegradation of basement membranes and remodeling of theextracellular matrix by proteolytic enzymes, includingmatrix metalloproteinases (MMPs) and tissue inhibitors ofmetalloproteinases (TIMPs). Objective: To evaluate the antiinvasiveeffect of imiquimod in human malignant melanomacell lines, SK-MEL-2 and SK-MEL-24, in vitro, and to investigateimiquimod-induced changes in the expression ofMMPs and TIMPs. Methods: Invasiveness of melanoma celllines following imiquimod treatment was evaluated byinvasion assays. In order to investigate the mechanism of theanti-invasive effect of imiquimod, mRNA and protein levelsof MMP-2, -9, membrane type 1 (MT1)-MMP, TIMP-1, and -2were assessed by real-time reverse transcription-polymerasechain reaction, gelatin zymography, and western blotting. Results: Imiquimod treatment decreased in vitro viability ofmelanoma cells in a concentration-dependent manner. Imiquimodalso elicited a concentration-dependent suppressionof invasion in both melanoma cell lines. A concentration-dependent decrease in MMP-2 and MT1-MMPprotein levels and a concentration-dependent increase inTIMP-1 and -2 protein levels by imiquimod was observed inboth melanoma cell lines. However, expression of MMP-9protein was increased in SK-MEL-2 but decreased inSK-MEL-24 with increasing imiquimod concentrations. Imiquimod elicited alterations in MMPs and TIMPs mRNAlevels that parallel the observed changes in protein levels. Conclusion: Imiquimod may elicit an anti-invasive effect onhuman melanoma cells by regulating MMPs and TIMPs.

참고문헌 (44)

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