Published ahead of print on October 10, 2008, doi:10.1164/rccm.200802-306OC Am. J. Respir. Crit. Care Med., Volume 179, Number 1, January 2009, 59-68 A more recent version of this article appeared on January 1, 2009
Submitted on February 20, 2008 A High Dietary Inorganic Phosphate Increases Lung Tumorigenesis and Alters Akt SignalingHua Jin1,1 Laboratory of Toxicology, Seoul National University, College of Veterinary Medicine, Seoul, Korea, Republic of; Center for Developmental Pharmacology and Toxicology, Seattle Children's Hospital Research Institute, Seattle, Washington, United States, 2 Laboratory of Toxicology, Seoul National University, College of Veterinary Medicine, Seoul, Korea, Republic of, 3 Laboratory of Toxicology, Seoul National University,College of Veterinary Medicine , Seoul, Korea, Republic of, 4 Laboratory of Toxicology, Seoul National University, College of Veterinary Medicine, Seoul, Korea, Republic of; National Core Research Center, Seoul National University, Nano Systems Institute, Seoul, Korea, Republic of, 5 Laboratory of Radiation Molecular Oncology, Korea Institute of Radiological & Medical Sciences, Seoul, Korea, Republic of, 6 Department of Food and Nutrition, Seoul National University, College of Human Ecology, Seoul, Korea, Republic of, 7 Pathology, Seoul National University, College of Veterinary Medicine, Seoul, Korea, Republic of, 8 Division of Endocrinology, Metabolism, and Lipids, Emory University School of Medicine, Atlanta, Georgia, United States, 9 Laboratory of Toxicology, Seoul National University, College of Veterinary Medicine, Seoul, Korea, Republic of; National Core Research Center, Seoul National University, Nano Systems Institute, Seoul, Korea, Republic of; National Institute of Toxicological Research, Korea Food and Drug Administration, Seoul, Korea, Republic of * To whom correspondence should be addressed. E-mail: mchotox{at}snu.ac.kr.
Rationale: Phosphate (Pi) is an essential nutrient to living organisms. Recent surveys indicate that the intake of Pi has increased steadily. Our previous studies have indicated that elevated Pi activates the Akt signaling pathway. An increased knowledge of the response of lung cancer tissue to high dietary Pi may provide an important link between diet and lung tumorigenesis. Objective: The current study was performed to elucidate the potential effects of high dietary Pi on lung cancer development. Methods: Experiments were carried out on 5-week-old male K-rasLA1 lung cancer model mice and 6-week-old male urethane-induced lung cancer model mice. Mice were fed a diet containing 0.5% Pi (normal Pi) and 1.0% Pi (high Pi) for 4 weeks. At the end of experiment, all mice were sacrificed. Lung cancer development was evaluated by diverse methods. Measurement and Main Results: A diet high Pi increased lung tumor progression and growth compared to normal diet. High dietary Pi increased the sodium-dependent inorganic phosphate transporter-2b protein levels in the lungs. High dietary Pi stimulated pulmonary Akt activity while suppressing the protein levels of tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 as well as Akt binding partner carboxyl-terminal modulator protein, resulting in facilitated cap-dependent protein translation. High dietary Pi also stimulated cell proliferation in the lungs of K-rasLA1 mice. Conclusion: Our results clearly demonstrated that high dietary Pi promoted tumorigenesis and altered Akt signaling, thus, suggesting that careful regulation of dietary Pi may be critical for lung cancer prevention as well as treatment. Key words: Inorganic phosphate • lung tumorigenesis • Akt signaling
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