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

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 concentrati...

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Bibliographic Details
Published in:International journal of molecular sciences 2021-09, Vol.22 (18), p.10096
Main Authors: Lacerda-Abreu, Marco Antonio, Russo-Abrahão, Thais, Rocco-Machado, Nathália, Cosentino-Gomes, Daniela, Dick, Claudia Fernanda, Carvalho-Kelly, Luiz Fernando, Cunha Nascimento, Michelle Tanny, Rocha-Vieira, Thaís Cristino, Meyer-Fernandes, José Roberto
Format: Article
Language:English
Subjects:
Acetylcysteine
Adhesion
Antioxidants
Breast cancer
breast cancer cells
Cell adhesion & migration
cell migration
Cell proliferation
Growth rate
H+-dependent Pi transport
Hydrogen peroxide
Mesenchyme
Metabolism
Metastases
Metastasis
Mitochondria
Na+-dependent Pi transport
NAD(P)H oxidase
Oxygen consumption
Pi-induced H2O2 production
Protein kinase C
Tumors
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Summary: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.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms221810096