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School of Medicine Publications and Presentations
High phosphate actively induces cytotoxicity by rewiring pro-survival and pro-apoptotic signaling networks in HEK293 and HeLa cells
Document Type
Article
Publication Date
1-2021
Abstract
Inorganic phosphate (Pi) is an essential nutrient for human health. Due to the changes in our dietary pattern, dietary Pi overload engenders systemic phosphotoxicity, including excessive Pi-related vascular calcification and chronic tissue injury. The molecular mechanisms of the seemingly distinct phenotypes remain elusive. In this study, we investigated Pi-mediated cellular response in HEK293 and HeLa cells. We found that abnormally high Pi directly mediates diverse cellular toxicity in a dose-dependent manner. Up to 10 mM extracellular Pi promotes cell proliferation by activating AKT signaling cascades and augmenting cell cycle progression. By introducing additional Pi, higher than the concentration of 40 mM, we observed significant cell damage caused by the interwoven Pi-related biological processes. Elevated Pi activates mitogen-activated protein kinase (MAPK) signaling, encompassing extracellular signal-regulated kinase 1/2 (ERK1/2), p38 and Jun amino-terminal kinase (JNK), which consequently potentiates Pi triggered lethal epithelial-mesenchymal transition (EMT). Synergistically, high Pi-caused endoplasmic reticulum (ER) stress also contributes to apparent apoptosis. To counteract, Pi-activated AKT signaling promotes cell survival by activating the mammalian target of rapamycin (mTOR) signaling and blocking ER stress. Pharmacologically or genetically abrogating Pi transport, the impact of high Pi-induced cytotoxicity could be reduced. Taken together, abnormally high extracellular Pi results in a broad spectrum of toxicity by rewiring complicated signaling networks that control cell growth, cell death, and homeostasis.
Recommended Citation
He, P., Mann‐Collura, O., Fling, J., Edara, N., Hetz, R., & Razzaque, M. S. (2021). High phosphate actively induces cytotoxicity by rewiring pro‐survival and pro‐apoptotic signaling networks in HEK293 and HeLa cells. The FASEB Journal, 35(1), e20997. https://doi.org/10.1096/fj.202000799RR
Publication Title
The FASEB Journal
DOI
https://doi.org/10.1096/fj.202000799RR
Academic Level
faculty
Mentor/PI Department
Molecular Science
Comments
© 2020 Federation of American Societies for Experimental Biology.
https://faseb.onlinelibrary.wiley.com/share/FPIDJ5YJT8EX6QZCQ2UF?target=10.1096/fj.202000799RR