Dual suppression of the MAP kinase and PI3K/Akt pathways showed synergistic or greatly enhanced anti-melanoma cell effects, compared to suppression of a single pathway, including the inhibition of cell proliferation, transformation and invasion, induction of G0/G1 cell cycle arrest and, importantly, cell apoptosis. Remarkably, suppression of either pathway induces the expression of thyroid iodide-handling genes and dual suppression of the two pathways synergistically and robustly induces expression of these genes, accompanied by uptake of radioiodine in the cells. These genes include sodium/iodide symporter, thyroid-stimulating hormone receptor, thyroglobulin, thyroperoxidase, pendrin gene, thyroid transcription factors (e.g., TTF-1, TTF-2, PAX8) and other thyroid genes. Targeting major signaling pathways, such as the MAP kinase and PI3K/Akt pathways, for potent cell death, optionally coupled with induction of thyroid gene expression for adjunct radioiodine ablation therapy may be used for many human cancers, both thyroid and non-thyroid.
