High Inorganic Phosphate Intake Promotes Tumorigenesis at Early Stages in a Mouse Model of Lung Cancer.
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.
Laboratory of Toxicology, BK21 PLUSProgram for Creative Veterinary Science Research, Research Institute for Veterinary Science and College of Veterinary Medicine, Seoul National University, Seoul, 151-742, Korea; Graduate Group of Tumor Biology, Seoul National University, Seoul, 151-742, Korea.
Somin
S
Lee
Laboratory of Toxicology, BK21 PLUSProgram for Creative Veterinary Science Research, Research Institute for Veterinary Science and College of Veterinary Medicine, Seoul National University, Seoul, 151-742, Korea.
Ji-Eun
JE
Kim
Laboratory of Toxicology, BK21 PLUSProgram for Creative Veterinary Science Research, Research Institute for Veterinary Science and College of Veterinary Medicine, Seoul National University, Seoul, 151-742, Korea.
Seong-Ho
SH
Hong
Laboratory of Toxicology, BK21 PLUSProgram for Creative Veterinary Science Research, Research Institute for Veterinary Science and College of Veterinary Medicine, Seoul National University, Seoul, 151-742, Korea.
Ah-Young
AY
Lee
Department of Molecular Science and Technology, Ajou University, Suwon, 443-749, Korea.
Eun-Jung
EJ
Park
Laboratory of Pathology, College of Veterinary Medicine, Seoul National University, Seoul, 151-742, Korea.
Hwi Won
HW
Seo
Laboratory of Pathology, College of Veterinary Medicine, Seoul National University, Seoul, 151-742, Korea.
Chanhee
C
Chae
Elemental Bio-imaging Facility, Department of Chemistry and Forensic Science, University of Technology, Sydney, Australia.
Philip
P
Doble
Elemental Bio-imaging Facility, Department of Chemistry and Forensic Science, University of Technology, Sydney, Australia.
David
D
Bishop
Laboratory of Toxicology, BK21 PLUSProgram for Creative Veterinary Science Research, Research Institute for Veterinary Science and College of Veterinary Medicine, Seoul National University, Seoul, 151-742, Korea; Graduate School of Convergence Science and Technology, Seoul National University, Suwon, 443-270, Korea; Graduate Group of Tumor Biology, Seoul National University, Seoul, 151-742, Korea; Advanced Institute of Convergence Technology, Seoul National University, Suwon, 443-270, Korea.
Myung-Haing
MH
Cho
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D010710:Phosphates / Q000008:administration & dosage / Q000009:adverse effects*; D016226:Phosphorus, Dietary / Q000008:administration & dosage / Q000009:adverse effects*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
D010710:Phosphates; D016226:Phosphorus, Dietary; D012333:RNA, Messenger; D051057:Proto-Oncogene Proteins c-akt