This Article Full Text Full Text (PDF) All Versions of this Article: 200802-306OCv1 179/1/59    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Jin, H. Articles by Cho, M.-H. Search for Related Content PubMed PubMed Citation Articles by Jin, H. Articles by Cho, M.-H.

High Dietary Inorganic Phosphate Increases Lung Tumorigenesis and Alters Akt Signaling

¹ Laboratory of Toxicology, and ⁶ Pathology, College of Veterinary Medicine, ³ Nano Systems Institute-National Core Research Center, and ⁵ Department of Food and Nutrition, College of Human Ecology, Seoul National University, Seoul, Korea; ² Center for Developmental Pharmacology and Toxicology, Seattle Children's Hospital Research Institute, Seattle, Washington; ⁴ Laboratory of Radiation Molecular Oncology, Korea Institute of Radiological & Medical Sciences, Seoul, Korea; ⁷ Division of Endocrinology, Metabolism, and Lipids, Emory University School of Medicine, Atlanta, Georgia; and ⁸ National Institute of Toxicological Research, Korea Food and Drug Administration, Seoul, Korea

Correspondence and requests for reprints should be addressed to Myung-Haing Cho, D.V.M., Ph.D., Laboratory of Toxicology, College of Veterinary Medicine, Seoul National University, Seoul 151-472, Korea. 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.

Objectives: The current study was performed to elucidate the potential effects of high dietary Pi on lung cancer development.

Methods: Experiments were performed on 5-week-old male K-ras^LA1 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 the experiment, all mice were killed. Lung cancer development was evaluated by diverse methods.

Measurement and Main Results: A diet high in Pi increased lung tumor progression and growth compared with normal diet. High dietary Pi increased the sodium-dependent inorganic phosphate transporter-2b protein levels in the lungs. High dietary consumption of 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. In addition, high dietary Pi significantly stimulated cell proliferation in the lungs of K-ras^LA1 mice.

Conclusions: Our results showed 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

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject The Akt pathway plays an important role in the lung tumorigenesis, and recent advances suggest that elevated Pi may activate the Akt signaling in the normal lungs. What This Study Adds to the Field High dietary inorganic phosphate strongly activates Akt signaling, and increased lung tumorigenesis. Careful regulation of dietary Pi may be critical for lung cancer prevention as well as treatment.