Low Dietary Inorganic Phosphate Stimulates Lung Tumorigenesis Through Altering Protein Translation and Cell Cycle in K-ras^LA1 Mice

Abstract

Recent surveys indicate that Pi intake has increased steadily as Pi-containing foods have increased. Our previous study demonstrated that high dietary Pi strongly stimulated lung tumorigeneis. In order to answer the issue whether low Pi may be chemopreventive, we examined the effects of low Pi on lung cancer. Eighteen 5-wk-old male K-ras ^LA1 lung cancer model mice were randomly allocated to 2 groups. One group was fed a normal diet (0.5% Pi) and other group was fed low Pi (0.1% Pi) diet for 4 wk. Lung cancer development was evaluated by histopathological examination, Western blot, kinase assay, and immunohistochemistry. Low Pi increased the expression of sodium-dependent phosphate co-transporter 2b, and activated Akt signal with decreased PTEN expression in the lungs of K-ras ^LA1 mice. Low Pi increased the Akt/mTOR-mediated protein translation through upregulating the phosphorylation of p70S6K and 4E-BP1. In addition, low Pi stimulated cell cycling as evidenced by altered cell cycle regulators such as cyclin D1 and D3. Finally, low Pi increased lung tumorigenesis in K-ras ^LA1 mice compared to the normal diet group. Our results clearly demonstrated that low Pi also promoted lung tumorigenesis, thus suggesting that an appropriate intake of dietary Pi may be critical for lung cancer prevention as well as treatment.

ACKNOWLEDGMENTS

Cheng-Xiong Xu and Hua Jin contributed equally to this work. This work was partially supported by the grants from the NRF (2010-0000784) of the Ministry of Science, Education, and Technology in Korea. M.-H. Cho was supported by the Nano Systems Institute–National Core Research Center (NSI-NCRC) program of KOSEF. H.-T. Lim was grateful for the award of the BK21 fellowship. K.-H. Lee was supported by the National Nuclear R&D Program from the Ministry of Science, Education, and Technology.

Notes

^aAbbreviations are as follows: Pi, phosphate; KH₂PO₄, monopatassium phosphate.

^bPi-free mixture.

^aNormal, normal Pi diet group; Low, low Pi diet group. Data are expressed as μean ± standard error of the mean; n = 9.

∗∗P < 0.01, highly significant compared to control.

^aNormal, normal diet group; Low, low phosphate diet group. Data are expressed as μean ± standard error of the mean.

∗∗P < 0.01, highly significant compared to control.

^bNumber of tumors of at least 1.5 μm in diameter.

^cNumber of tumors of smaller than 1.5 μm in diameter.