Phosphate (Pi) is an indispensable nutrient for all living creatures. It is essential for numerous biological processes, notably osteoblast differentiation and bone mineralization.
The maintenance of correct Pi homeostasis is crucial, as any variation from this state can result in various acute and chronic illness states, as well as influence the aging process and lifespan.
The serum Pi level is regulated within a restricted range through a complicated interplay between absorption, exchange with intracellular and bone storage pools, renal tubular reabsorption, and the activity of Na/Pi cotransporters.
Pi is plentiful in the diet, and intestinal absorption is efficient and little regulated. The kidney is a key regulator of Pi homeostasis and can enhance or decrease its Pi reabsorptive capacity to meet Pi requirements.
Pi is emerging as a key signaling molecule capable of influencing several physiological activities by modifying signal transduction pathways, gene expression, and protein abundance in numerous cell types.
However, little is known about the first steps involving the changing in serum or local Pi levels and the ensuing cascade of downstream regulation.
Previously, we demonstrated that Pi reduces the proliferation and aggressiveness of human osteosarcoma U2OS cells by identifying adenylate cyclase, beta3 integrin, Rap1, and ERK1/2 as proteins whose production and Pi significantly alter function.
Recently, we discovered that Pi could also sensitize osteosarcoma cells to doxorubicin in a p53-dependent way and via a mechanism involving the downregulation of ERK1/2.
This paper outlines the current understanding of inorganic phosphate as a novel unique signaling chemical in bone and other mammalian cell types. It discusses how targeting Pi levels in local areas may offer a technique for enhancing osteosarcoma treatment.
Numerous chronic disorders, including cancer, have been hypothesized to be linked to excessive phosphorus consumption and high inorganic phosphate (Pi) concentrations in the blood.
On the other hand, there is evidence that Pi can have an antitumor effect on some cancer cell types, depending on the cell status and genetic background, and achieve an admixture cytotoxic effect when compared with doxorubicin, demonstrating its potential for clinical applications and indicating that up-regulating Pi levels at local sites for brief periods could contribute to the development of novel and inexpensive modalities for treatment in some tumors, including melanoma.
Inorganic Phosphate And Cancer
Inorganic phosphate is among the most crucial minerals for living organisms (Pi). ATP generation, kinase/phosphatase signaling, and synthesizing lipids, carbohydrates, and nucleic acids all require it. In addition, it is essential for proper skeletal and dentin mineralization.
Diet is the primary source of Pi, and intestinal absorption is barely restricted and normally extends to around 70 percent. An intricate network including the intestine, kidney, parathyroid gland, and bone is involved in a feedback regulation involving hormones such as parathyroid hormone (PTH), 1,25-dihydroxy vitamin D, and fibroblast growth factor 23 (FGF-23) as primary regulators of Pi homeostasis.
Due to highly processed foods, notably restaurant meals, fast foods, and inexpensive foods, phosphorus intake has increased.
In the United States, the average daily intake of phosphorus from food is approximately 1,400 mg, as inorganic phosphate (Pi) salts or organic molecules, nearly double the adult recommended dietary requirement.
The kidney is one of the primary regulators of Pi homeostasis and can increase or decrease its ability to reabsorb Pi; the longitudinal study found usage of Pi-containing components in food processing has been demonstrated to be potentially hazardous when nutrient requirements are exceeded.
Several recent investigations have shown the association between a high Pi intake/high Pi serum levels and morbidity and mortality.
Chronic high-Pi diets have been linked to several illnesses and diseases, primarily cardiovascular disorders, in persons with high Pi consumption.
Other chronic disorders, such as type 2 diabetes mellitus, obesity, and cancer, have also been linked to high Pi intakes and serum concentrations.
The methods through which high Pi concentrations are associated with tissue damage and may impact tumor formation are not fully known but are likely to involve a combination of cell-autonomous, autocrine, paracrine, and endocrine signals.
Particularly, although both PTH and FGF-23 are stimulated to decrease the post-meal serum Pi concentration rise by approximately 1 h via the interruption of renal Pi reabsorption, it is hypothesized that if cells are exposed to even a brief high-serum Pi concentration, signal alterations in cell functions could occur, resulting in negative effects. In addition, increased serum levels of FGF-23 or PTH may be hazardous to specific cell types.
There may be a phosphate-sensing system able to detect serum and local phosphate fluctuations and notify the body, the local environment, or the particular cell, as supported by numerous recent studies.
Because the intracellular environment is more electronegative than the external environment, Pi entry into the cell is facilitated by Na+-coupled Pi cotransporters, a controlled process.
In addition, Pi is emerging as a crucial signaling molecule capable of modulating many physiological activities via altering signal transduction pathways, gene expression, and protein levels in numerous cell types.
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