TITLE: Notch1-MAPK Signaling Axis Regulates CD133+ Cancer Stem Cell-Mediated Melanoma Growth and Angiogenesis
Functional characterization and understanding of the intricate signaling mechanisms in stem like cells is crucial for the development of effective therapies in melanoma. We have studied whether melanoma cells are phenotypically distinct and hierarchically organized according to their tumorigenic nature. We report that melanoma-specific CD133+ cancer stem cells exhibit increased tumor-initiating potential, tumor-endothelial cell interaction and lung metastasis. These cells are able to trans-differentiate into an endothelial-like phenotype when cultured under endothelial differentiation-promoting conditions. Mechanistically, Notch1 upregulates MAPK activation through CD133, which ultimately controls VEGF and MMP expression in CD133+ stem cells leading to melanoma growth, angiogenesis and lung metastasis. Blockade or genetic ablation of Notch1 and MAPK pathways abolishes melanoma cell migration and angiogenesis. ChIP and reporter assays revealed that NICD1 regulates CD133 expression at the transcriptional level. Andrographolide inhibits NICD1 expression, NICD1-dependent CD133-mediated MAPK and AP-1 activation, and epithelial to mesenchymal-specific gene expression, ultimately attenuating melanoma growth and lung metastasis. Human malignant melanoma specimen analyses revealed a strong correlation between NICD1, CD133 and p-p38 MAPK expression and malignant melanoma progression. Thus, targeting Notch1 and its regulated signaling network may have potential therapeutic implications for the management of CSC-mediated melanoma progression.
Dhiraj Kumar, Santosh Kumar, Mahadeo Gorain, Deepti Tomar, Harshal S. Patil, N.N.V. Radharani, T.V.S. Kumar, Tushar V. Patil, H.V. Thulasiram, Gopal C. Kundu