Inorganic phosphate (Pi) is a vital nutrient for all living things. It plays a crucial role in various physiological processes such as energy metabolism, lipid biosynthesis, nucleic acid biosynthesis, cellular differentiation, cellular repair and cellular signaling 1,2. The main source of Pi intake for humans is the diet, where Pi exists in one of three anionic forms; HPO42-, H2PO4- or H3PO4 2. In the body, serum Pi levels are precisely maintained within a specific range via the interplay between several organs including intestine, kidney, parathyroid gland and bones. Similarly, extracellular Pi levels are maintained within a narrow range; between 0.7 and 1.55 mM 2–4.
Many studies have proposed the existence of a phosphate sensing mechanism in the body capable of detecting both serum and extracellular phosphate fluctuations and subsequently relaying this information to the cells, the local environment and/or the whole body 5–7. Interestingly, several findings have revealed that extracellular phosphate in itself carries out this function by acting as a signaling molecule 6, 8–12. The interior environment of the cell is electronegative compared to the exterior one, thus, the transport of Pi into the cell does not happen by simple diffusion, but instead is mediated by Na+-coupled Pi cotransporters, which are highly regulated proteins 4,5,13. Furthermore, Pi can initiate signal transduction pathways, alter gene expression and regulate diverse cellular functions 7,9,14,15. All these evidence serve to pinpoint the importance of Pi in the body and to highlight the significance of regulating Pi levels.
Recently, high Pi intake and high Pi serum levels were associated with higher morbidity and mortality rates 16,17. In fact, high serum concentrations are associated with kidney disease, perturbed brain growth, vascular calcification and cardiovascular events 16–19. However, the mechanisms by which high Pi concentrations are linked to tissue damage are not completely understood. Shuto et.al showed that Pi acutely impairs endothelial function by increasing production of reactive oxygen species and decreasing production of nitric oxide 20. On the other hand, how phosphate affects diseased cells, particularly cancer cells, is only minimally explored 21,22. For instance, Spina et.al demonstrated that Pi inhibits proliferation of human osteosarcoma U2OS cells as well as MDA-MB-231 cells but did not explore its effect on normal, healthy cells 14,23,24.
In this study, we investigated the toxicity of different phosphate compounds to triple-negative human breast cancer cells (MDA-MB-231) and to human monocytes (THP-1). We demonstrated that, unlike phosphate in the form of dihydrogen phosphate (H2PO4−), hydrogen phosphate (HPO42−) induces breast cancer cell death but not immune cell death. We attribute this effect to the fact that phosphate in the form of HPO42− raises pH levels to alkaline levels which are not optimum for phosphate transport into cancer cells. Taken together, these results indicate the significance of further exploring HPO42− as potential therapeutic for the treatment of breast cancer.