Chemopreventive and bioenergetic signaling effects of PDK1/Akt pathway inhibition in a transgenic mouse model of prostate cancer.
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 model prostate (TRAMP) mouse 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.
Sargeant
Aaron M
AM
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210-1291, USA.
Klein
Russell D
RD
Rengel
Robert C
RC
Clinton
Steven K
SK
Kulp
Samuel K
SK
Kashida
Yoko
Y
Yamaguchi
Mamoru
M
Wang
Xingya
X
Chen
Ching-Shih
CS
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000230:Adenocarcinoma / Q000473:pathology* / Q000503:physiopathology / Q000517:prevention & control*; D000273:Adipose Tissue / Q000187:drug effects; D000818:Animals; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004848:Epithelium / Q000473:pathology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D018656:Muscle Fibers, Fast-Twitch / Q000187:drug effects / Q000473:pathology; D009336:Necrosis / Q000139:chemically induced / Q000473:pathology; D009929:Organ Size; D011467:Prostate / Q000473:pathology; D011471:Prostatic Neoplasms / Q000473:pathology* / Q000503:physiopathology / Q000517:prevention & control*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects*
D004791:Enzyme Inhibitors; D064413:3-Phosphoinositide-Dependent Protein Kinases; D000071679:Glycogen Synthase Kinase 3 beta; C578564:Pdpk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3