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DOI: 10.1080/01926230701338966 © 2007 Society of Toxicologic Pathology
Chemopreventive and Bioenergetic Signaling Effects of PDK1/Akt Pathway Inhibition in a Transgenic Mouse Model of Prostate Cancer
1 Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy Correspondence: Address correspondence to: Ching-Shih Chen, College of Pharmacy, 336 Parks Hall, The Ohio State University, 500 West 12th Avenue, Columbus, OH 43210-1291; e-mail:chen.844{at}osu.edu The phosphoinositide-dependent kinase 1 (PDK1)/Akt pathway is an important regulator of multiple biological processes including cell growth, survival, and glucose metabolism. In light of the mechanistic link between Akt signaling and prostate tumorigenesis, we evaluated the chemopreventive relevance of inhibiting this pathway in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model with OSU03012, a celecoxib-derived, but COX-2-inactive, PDK1 inhibitor. Beginning at ten weeks of age when prostatic intraepithelial neoplasia (PIN) lesions are well developed, TRAMP mice received OSU03012 via daily oral gavage for 8 weeks. The drug treatment significantly decreased the weight of all 4 prostate lobes as well as the grade of epithelial proliferation in the dorsal and lateral lobes compared to vehicle-treated control mice. The incidences of carcinoma and metastasis were decreased, although not to statistically significant levels. Treated mice lost body fat and failed to gain weight independent of food intake. This change and periportal hepatocellular atrophy can be linked to sustained PDK1 inhibition through downstream inactivation of glycogen synthase. Centrilobular hepatocellular hypertrophy and necrosis of Type II skeletal myofibers were also compound-related effects. We conclude that targeting of the PDK1/Akt pathway has chemopreventive relevance in prostate cancer and causes other in vivo effects mediated in part by an alteration of bioenergetic signaling.
Key Words: OSU03012 • TRAMP • prostate • PDK1 • Akt • chemoprevention • myonecrosis Abbreviations: PI3K, phosphatidylinositol 3-kinase • PDK1, phosphoinositide-dependent kinase 1 • TRAMP, transgenic adenocarcinoma of the mouse prostate • PIN, prostatic intraepithelial neoplasia • GSK3β, glycogen synthase kinase 3 beta • GS, glycogen synthase • AST, aspartate aminotransferase • CK, creatine kinase • ALT, alanine aminotransferase • ALP, alkaline phosphatase • COX-2, cyclooxygenase-2 • PAS, periodic acid-Schiff • H&E, hematoxylin and eosin • S6K, p70 ribosomal S6 kinase • MHC, myosin heavy chain • ER, endoplasmic reticulum
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