Abstract
[Objective]
Malignant melanoma shows aggressive and highly metastatic features. In particular, metastasis markedly exacerbates prognosis of melanoma patients. Currently, there are few effective measures to improve prognosis of patients with metastasis and novel therapeutic agents are urgently required. We showed that differentiation-inducing factor-1 (DIF-1) isolated from Dictyostelium discoideum strongly inhibited the proliferation of various cancer cells including melanoma. And moreover, we found that DIF-1 strongly prevented lung colony formation in mouse models of metastatic melanoma. However, the mechanism of this action of DIF-1 remains to be elucidated. In the present study, we investigated the effect of DIF-1 on migration and invasion of melanoma cells, because they are essential for distant metastasis.
[Methods]
Using human malignant melanoma cell line A2058, activities of cell migration and invasion were measured by the wound healing assay and cell invasion assay, respectively. Expressions of the signaling molecules were measured by Western blotting.
[Results and Conclusion]
DIF-1 significantly inhibited cell migration and invasion in a time- and concentration-dependent manner. Activation of Janus kinase (JAK)-signal transducer and activator of transcription 3 (Stat3) is one of the crucial signals for cancer progression and metastasis. DIF-1 markedly suppressed the phosphorylation levels of Stat3 after 6 hours of incubation. Stat3 induces a variety of genes related to cell migration and invasion such as matrix metalloproteinase-2 (MMP-2), vimentin, N-cadherin, and twist. All of their expressions were markedly reduced by DIF-1 after 12 hours incubation. These results suggested that DIF-1 inhibits cell migration and invasion by the inhibition of Stat3 phosphorylation in malignant melanoma and therefore that DIF-1 has potential to be a lead chemical compound for developing a novel anti-tumor agent for treating malignant melanoma.
