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Hydrogen Peroxide Generation as an Underlying Response to High Extracellular Inorganic Phosphate (Pi) in Breast Cancer Cells.

ABSTRACT: According to the growth rate hypothesis (GRH), tumour cells have high inorganic phosphate (Pi) demands due to accelerated proliferation. Compared to healthy individuals, cancer patients present with a nearly 2.5-fold higher Pi serum concentration. In this work, we show that an increasing concentration of Pi had the opposite effect on Pi-transporters only in MDA-MB-231 when compared to other breast cell lines: MCF-7 or MCF10-A (non-tumoural breast cell line). Here, we show for the first time that high extracellular Pi concentration mediates ROS production in TNBC (MDA-MB-231). After a short-time exposure (1 h), Pi hyperpolarizes the mitochondrial membrane, increases mitochondrial ROS generation, impairs oxygen (O₂) consumption and increases PKC activity. However, after 24 h Pi-exposure, the source of H₂O₂ seems to shift from mitochondria to an NADPH oxidase enzyme (NOX), through activation of PKC by H₂O₂. Exogenous-added H₂O₂ modulated Pi-transporters the same way as extracellular high Pi, which could be reversed by the addition of the antioxidant N-acetylcysteine (NAC). NAC was also able to abolish Pi-induced Epithelial-mesenchymal transition (EMT), migration and adhesion of MDA-MB-231. We believe that Pi transporters support part of the energy required for the metastatic processes stimulated by Pi and trigger Pi-induced H₂O₂ production as a signalling response to promote cell migration and adhesion.

SUBMITTER: Lacerda-Abreu MA

PROVIDER: S-EPMC8468810 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Reactive Oxygen Species (ROS) are a natural byproduct of oxygen metabolism. At physiological levels, ROS regulate multiple cellular processes like proliferation, migration, and differentiation. Increased levels of ROS are associated with pathological conditions, such as inflammation and vascular calcification, where they elicit cytotoxic effects. These contrasting outcomes of ROS have also been reported in osteogenic precursor cells. However, the role of ROS in committed osteogenic cells has not been investigated. Cytotoxic and physiologic effects have also been demonstrated for extracellular phosphate (Pi). Specifically, in committed osteogenic cells Pi stimulates their major function (mineralization), however in osteogenic precursors and endothelial cells Pi cytotoxicity has been reported. Interestingly, Pi cytotoxic effects have been associated with ROS production in the pathological vascular mineralization. In this study, we investigated a molecular mechanistic link between elevated Pi and ROS production in the context of the mineralization function of committed osteogenic cells. Using committed osteogenic cells, 17IIA11 odontoblast-like cell and MLO-A5 osteoblast cell lines, we have unveil that Pi enhances intracellular ROS production. Furthermore, using a combination of mineralization assays and gene expression analyses, we determined that Pi-induced intracellular ROS supports the physiological mineralization process. In contrast, the exogenous ROS, provided in a form of H2O2, was detrimental for osteogenic cells. By comparing molecular signaling cascades induced by extracellular ROS and Pi, we identified differences in signaling routes that determine physiologic versus toxic effect of ROS on osteogenic cells. Specifically, while both extracellular and Pi-induced intracellular ROS utilize Erk1/2 signaling mediator, only extracellular ROS induces stress-activated mitogen-activated protein kinases P38 and JNK that are associated with cell death. In summary, our results uncovered a physiological role of ROS in the Pi-induced mineralization through the molecular pathway that is distinct from ROS-induced cytotoxic effects.

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Hydrogen Peroxide Generation as an Underlying Response to High Extracellular Inorganic Phosphate (Pi) in Breast Cancer Cells.

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