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.