Inhibition of Wnt signaling downregulates Akt activity and induces chemosensitivity in PTEN-mutated prostate cancer cells.
BACKGROUND
The cross-talk between Wnt signaling and the Akt pathway in prostate cancer (Pca) is still unclear. In the present study, we found that WIF-1 downregulates the Akt pathway and also enhances chemosensitivity in PTEN-null Pca cells.


METHODS
Wnt inhibitory factor-1 (WIF-1), an inhibitor of Wnt proteins, was transfected into PC-3 and DU145 Pca cells.


RESULTS
Akt was phosphorylated in PTEN-null PC-3 cells but underphosphorylated in PTEN-expressed DU145 cells. The levels of phosphorylated Akt in WIF-1 overexpressing PC-3 cells were lower than those in native or control vector-transfected PC-3 cells. However, WIF-1 showed no additional inhibition of already reduced Akt activity in DU145 cells. Overexpression of WIF-1 resulted in sensitizing PC-3 cells for paclitaxel to induce apoptosis. DU145 cells were more sensitive to paclitaxel but were not affected by WIF-1 transfection. The PI3K inhibitor LY294002 seemed to restore the chemosensitivity of native PC-3 cells like WIF-1 did.


CONCLUSIONS
Our results show that Wnt signaling is involved in Akt activation in Pca cells. Our data also indicate the possibility that Wnt and its signaling pathway can be therapeutic targets for PTEN-mutated advanced Pca.
Ohigashi
T
T
Department of Urology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. ohigashi@sc.itc.keio.ac.jp
Mizuno
R
R
Nakashima
J
J
Marumo
K
K
Murai
M
M
D048868:Adaptor Proteins, Signal Transducing; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D017209:Apoptosis; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins / Q000378:metabolism; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D015870:Gene Expression / Q000502:physiology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008297:Male; D009154:Mutation; D051059:PTEN Phosphohydrolase; D017239:Paclitaxel / Q000627:therapeutic use; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics; D051176:beta Catenin
D048868:Adaptor Proteins, Signal Transducing; D000972:Antineoplastic Agents, Phytogenic; C495270:CTNNB1 protein, human; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; C485569:WIF1 protein, human; D051176:beta Catenin; C494918:AKT1 protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D017239:Paclitaxel