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

• Published in: Nutrition and cancer 2010-01, Vol.62 (4), p.525-532
• Main Authors: Xu, Cheng-Xiong, Jin, Hua, Lim, Hwang-Tae, Ha, Yoon-Cheol, Chae, Chan-Hee, An, Gil-Hwan, Lee, Kee-Ho, Cho, Myung-Haing
• Format: Article
• Language: English
• Subjects: Adenoma - pathology; animal models; Animals; carcinogenesis; Carrier Proteins - metabolism; Cell Cycle; Cell Cycle Proteins - metabolism; chemoprevention; dietary minerals; Genes, ras; histopathology; Hyperplasia - pathology; immunohistochemistry; inorganic phosphorus; Intracellular Signaling Peptides and Proteins - metabolism; lung neoplasms; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Lung Neoplasms - prevention & control; Male; Mice; nutritional intervention; Phosphoproteins - metabolism; Phosphorus, Dietary - administration & dosage; Phosphorylation; Protein Biosynthesis; Protein-Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins c-akt - metabolism; PTEN Phosphohydrolase - metabolism; Random Allocation; Ribosomal Protein S6 Kinases, 70-kDa - metabolism; Signal Transduction; Sodium-Phosphate Cotransporter Proteins, Type IIb - metabolism; TOR Serine-Threonine Kinases; Tumor Burden
• ISSN: 0163-5581; 1532-7914
• DOI: 10.1080/01635580903532432

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.