Abstract
Inorganic phosphate (Pi) is required by all living organisms for the development of organs such as bone, muscle, brain, and lungs, regulating the expression of several critical genes as well as signal transduction. However, little is known about the effects of prolonged dietary Pi consumption on lung cancer progression. This study investigated the effects of a high-phosphate diet (HPD) in a mouse model of adenocarcinoma. K-rasLA1 mice were fed a normal diet (0.3% Pi) or an HPD (1% Pi) for 1, 2, or 4 months. Mice were then sacrificed and subjected to inductively coupled plasma mass/optical emission spectrometry and laser ablation inductively coupled plasma mass-spectrometry analyses, western blot analysis, histopathological, immunohistochemical, and immunocytochemical analyses to evaluate tumor formation and progression (including cell proliferation, angiogenesis, and apoptosis), changes in ion levels and metabolism, autophagy, epithelial-to-mesenchymal transition, and protein translation in the lungs. An HPD accelerated tumorigenesis, as evidenced by increased adenoma and adenocarcinoma rates as well as tumor size. However, after 4 months of the HPD, cell proliferation was arrested, and marked increases in liver and lung ion levels and in energy production via the tricarboxylic acid cycle in the liver were observed, which were accompanied by increased autophagy and decreased angiogenesis and apoptosis. These results indicate that an HPD initially promotes but later inhibits lung cancer progression because of metabolic adaptation leading to tumor cell quiescence. Moreover, the results suggest that carefully regulated Pi consumption are effective in lung cancer prevention.
Highlights
Inorganic phosphate (Pi) is required by all living organisms for diverse cellular functions— including mineral metabolism and energy production from membrane phospholipids and nucleotides—and as a substrate for phosphorylated intermediates in cell signaling [1]
There have been no studies to date evaluating homeostatic maintenance in the lungs in relation to an highphosphate diet (HPD) or the role of Pi in metabolic adaptation and cancer progression, which involves autophagy, apoptosis, ion level regulation, and adenosine triphosphate (ATP) synthesis via the tricarboxylic acid (TCA) cycle
The results indicate that an HPD initially promotes but later inhibits lung cancer progression as a result of metabolic adaptation leading to tumor cell quiescence
Summary
Inorganic phosphate (Pi) is required by all living organisms for diverse cellular functions— including mineral metabolism and energy production from membrane phospholipids and nucleotides—and as a substrate for phosphorylated intermediates in cell signaling [1]. Pi can be acquired passively through food intake or actively via cellular metabolism. It is often used as a food additive not for health reasons, but for functions such as maintaining food color and flavor, acid buffering, leavening, texture stabilization, and prolongation of shelf life. There have been no studies to date evaluating homeostatic maintenance in the lungs in relation to an HPD or the role of Pi in metabolic adaptation and cancer progression, which involves autophagy, apoptosis, ion level regulation, and adenosine triphosphate (ATP) synthesis via the tricarboxylic acid (TCA) cycle. The results indicate that an HPD initially promotes but later inhibits lung cancer progression as a result of metabolic adaptation leading to tumor cell quiescence
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