Simultaneous suppression of MITF and BRAF^V600E enhanced inhibition of melanoma cell proliferation

Authors: Kido, Kenji; Sumimoto, Hidetoshi; Asada, Sakiyo¹; Okada, Starlyn M.¹; Yaguchi, Tomonori¹; Kawamura, Naoshi¹; Miyagishi, Makoto²; Saida, Toshiaki³; Kawakami, Yutaka

Source: Cancer Science, Volume 100, Number 10, October 2009 , pp. 1863-1869(7)

Publisher: Wiley-Blackwell

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Abstract:

Microphthalmia-associated transcription factor (MITF) is a master gene regulating differentiation of melanocytes, and a lineage survival oncogene mediating pro-proliferative function in malignant melanoma. However, high expression of MITF also has an anti-proliferative effect. To clarify the therapeutic implication of MITF as a molecular target for human melanoma, we evaluated the role of MITF in cell proliferation in a panel of human melanoma cell lines which express different levels of MITF. We found that both MITF depletion and forced expression of MITF significantly inhibited proliferation, suggesting that endogenous MITF is regulated at an appropriate level for melanoma cell proliferation, and could be a molecular target for melanoma. However, half of the melanoma cell lines in this study were relatively resistant to MITF depletion, indicating other treatment strategies are required for therapy. Our microarray analysis indicated that regulation of several cell growth-associated molecules may be independent of MITF and dependent on BRAF^V600E. Thus to enhance the anti-proliferative effect of MITF down-regulation, we combined shRNA-mediated MITF depletion with BRAF^V600E inactivation, another known molecular target for melanoma. Indeed, simultaneous depletion of both MITF and BRAF^V600E significantly inhibited melanoma growth even for the melanoma cell lines resistant to MITF depletion. These results suggest MITF may be an important molecular target for human melanoma and simultaneous inhibition of MITF and MAPK signaling may be an attractive strategy for melanoma treatment. (Cancer Sci 2009; 100: 1863-1869)

Document Type: Research article

DOI: http://dx.doi.org/10.1111/j.1349-7006.2009.01266.x

Affiliations: 1: Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Shinjuku-ku, Tokyo 2: Department of Gene Diagnostics and Therapeutics, Research Institute, International Medical Center of Japan, Shinjuku-ku, Tokyo, Japan 3: Department of Dermatology, Shinshu University School of Medicine, Matsumoto City, Nagano

Publication date: 2009-10-01