Department of Biochemistry, Lake Erie College of Osteopathic Medicine, Erie, PA, USA.
Department of Pathology, Lake Erie College of Osteopathic Medicine, Erie, PA, USA.
Adv Exp Med Biol. 2022;1362:73-84. doi: 10.1007/978-3-030-91623-7_8.
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.
在包括代谢、骨骼、心脏、肾脏和各种癌症在内的疾病状态中，磷酸盐摄入不足或过量的潜在作用是显而易见的。升高的磷酸盐水平可诱导上皮细胞向间充质转化（EMT）和细胞死亡。众所周知，EMT 和相关的致命、转移性或纤维蛋白原性反应是纤维化疾病和各种实体瘤中潜在的疾病过程。研究表明，EMT 受不同信号通路的诱导调节，包括 TGF-β、RTK、SRC、Wnt 和 Notch 信号转导。然而，这些信号通路之间的串扰知之甚少。我们已经表明，升高的磷酸盐水平通过激活 ERK1/2 途径部分增强 EMT，导致大量细胞死亡。因此，我们提出过量磷酸盐介导的致命 EMT 是磷酸盐诱导细胞毒性的潜在机制之一，这可以解释临床前和临床研究中高磷酸盐相关的肾纤维化和癌症转移。本章概述了 EMT，并重点介绍了磷酸盐毒性诱导的各种信号通路对 EMT 的调节。我们进一步将最近报道的致命 EMT 置于磷酸盐毒性的背景下，旨在解释其与过量磷酸盐相关的病理。
