Low dietary inorganic phosphate stimulates lung tumorigenesis through altering protein translation and cell cycle in K-ras(LA1) mice.
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.
Xu
Cheng-Xiong
CX
Seoul National University, Seoul, Korea.
Jin
Hua
H
Lim
Hwang-Tae
HT
Ha
Yoon-Cheol
YC
Chae
Chan-Hee
CH
An
Gil-Hwan
GH
Lee
Kee-Ho
KH
Cho
Myung-Haing
MH
D048868:Adaptor Proteins, Signal Transducing; D000236:Adenoma / Q000473:pathology; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism; D039642:Eukaryotic Initiation Factors; D011905:Genes, ras; D006965:Hyperplasia / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000517:prevention & control; D008297:Male; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D016226:Phosphorus, Dietary / Q000008:administration & dosage*; D010766:Phosphorylation; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011897:Random Allocation; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction; D050614:Sodium-Phosphate Cotransporter Proteins, Type IIb / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D047368:Tumor Burden
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C499527:Eif4ebp1 protein, mouse; D039642:Eukaryotic Initiation Factors; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D016226:Phosphorus, Dietary; C493558:Slc34a2 protein, mouse; D050614:Sodium-Phosphate Cotransporter Proteins, Type IIb; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse