Phosphate Toxicity and Epithelial to Mesenchymal Transition.

The underlying role of inadequate or excess intake of phosphate is evident in disease states, including metabolic, skeletal, cardiac, kidney and various cancers. Elevated phosphate levels can induce epithelial to mesenchymal transition (EMT) and cell death. EMT and associated lethal, metastatic or fibrinogenic responses are known to be underlying disease processes in fibrotic diseases and various solid tumors. Studies have shown EMT is regulated by induction of different signaling pathways, including TGF-β, RTK, SRC, Wnt and Notch signal transduction. However, cross-talk amongst these signaling pathways is less understood. We have shown that elevated phosphate levels enhanced EMT partially through activating ERK1/2 pathway, resulting in massive cell death. We thus proposed excess phosphate-mediated lethal EMT as one of the underlying mechanisms of phosphate-induced cytotoxicity, which could explain high phosphate-associated renal fibrosis and cancer metastasis in preclinical and clinical studies. This chapter provides the overview of EMT with the highlights of its regulation by various signaling pathways induced by phosphate toxicity. We further put lately reported lethal EMT in the context of phosphate toxicity with the intent to explain it to excessive phosphate-associated pathologies.