High Inorganic Phosphate Intake Promotes Tumorigenesis at Early Stages in a Mouse Model of Lung Cancer

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.

High phosphate actively induces cytotoxicity by rewiring pro‐survival and pro‐apoptotic signaling networks in HEK293 and HeLa cells

“…Studies in mice have suggested positive correlations between high serum Pi and cancer. [19][20][21] In the JB6 mouse model, a high Pi diet resulted in cell transformation and skin tumorigenesis by stimulating N-Ras and downstream ERK1/2 phosphorylation. 19 In K-ras LA1 mice, elevated Pi promoted lung cancer progression at an early stage by stimulating cell proliferation and angiogenesis.…”

Elevated phosphate mediates extensive cellular toxicity: from abnormal proliferation to excessive cell death

“…Pi has been identified as an essential nutrient for cell growth(Chang et al, 2006, Conrads et al, 2005) and proliferation(Roussanne et al, 2001). Its potential roles in tumor development have been implicated in in cancers of breast(Lin, McKinnon et al, 2015), lung(Jin et al, 2009, Lee et al, 2015), skin(Camalier et al, 2010) and kidney(Brown & Razzaque, 2018). Paradoxically, lines of evidence also demonstrate Pi overload has systematically detrimental effects such as cardiovascular disorders(Tonelli et al, 2005) and renal dysfunction(Marks et al, 2013).…”

“…In JB6 mice model, a high Pi diet resulted in cell transformation and skin tumorigenesis by stimulating N-Ras and downstream ERK1/2 phosphorylation(Jin et al, 2009). In K-ras LA1 mice, elevated Pi promoted lung cancer progression at early stage by stimulating cell proliferation and angiogenesis(Lee et al, 2015). On the other hand, evidence also showed Pi’s toxic effects of triggering cell death(Di Marco, Hausberg et al, 2008) and tissue damage(Nakatani, Sarraj et al, 2009, Yoshikawa, Yamamoto et al, 2018, Zhang, Yang et al, 2018).…”

Lack of Awareness of Dietary Sources of Phosphorus Is a Clinical Concern

“…This result suggests that a standard soda drink can even influence individuals with normal renal function (24). Moreover, dietary phosphorus overload may be related to various kinds of malignancies such as lung, breast and prostate cancers, since phosphorus burden influences cancer cell growth and metabolism (3,25,26). However, the results of earlier studies have not always been consistent and further research is needed to clarify the underlying molecular connections.…”