5 years ago

1-Benzyl-indole-3-carbinol is a highly potent new small molecule inhibitor of Wnt/βcatenin signaling in melanoma cells that coordinately inhibits cell proliferation and disrupts expression of Microphthalmia Associated Transcription Factor isoform M.

Aryana, Khouri, Firestone, Kundu
1-Benzyl-indole-3-carbinol (1-benzyl-I3C), a synthetic analogue of the crucifer derived natural phytochemical I3C, displayed significantly wider sensitivity and anti-proliferative potency in melanoma cells than the natural compound. Unlike I3C, which targets mainly oncogenic BRAF-expressing cells, 1-benzyl I3C effectively inhibited proliferation of melanoma cells with a more extensive range of mutational profiles, including those expressing wild type BRAF. In both cultured melanoma cell lines and in vivo in melanoma cell-derived tumor xenografts, 1-benzyl-I3C disrupted canonical Wnt/β-catenin signaling that resulted in the down regulation of β-catenin protein levels with a concomitant increase in levels of the β-catenin destruction complex components GSK3β and Axin. Concurrent with the inhibition of Wnt/β-catenin signaling, 1-benzyl-I3C strongly down regulated expression of the melanoma master regulator, Microphthalmia Associated Transcription Factor isoform-M (MITF-M) by inhibiting promoter activity through the consensus LEF-1/TCF DNA binding site. Chromatin immunoprecipitation revealed that 1-benzyl-I3C down regulated interactions of endogenous LEF-1 with the MITF-M promoter. 1-Benzyl I3C ablated Wnt-activated LEF1-dependent reporter gene activity in a TOP FLASH assay that was rescued by expression of a constitutively active form of the Wnt co-receptor LRP6, indicating that 1-benzyl-I3C disrupts Wnt/β-catenin signaling at or upstream of LRP6. In oncogenic BRAF-expressing melanoma cells, combinations of 1-benzyl I3C and Vemurafenib, a clinically employed BRAF inhibitor, showed strong anti-proliferative effects. Taken together, our observations demonstrate that 1-benzyl-I3C represents a new and highly potent indolecarbinol-based small molecule inhibitor of Wnt/β-catenin signaling that has intriguing translational potential, alone or in combination with other anti-cancer agents, to treat human melanoma.

Publisher URL: http://doi.org/10.1093/carcin/bgx103

DOI: 10.1093/carcin/bgx103

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