Perifosine induces differentiation and cell death in prostate cancer cells.
We analyzed the mechanism of action for perifosine (D-21266), a new synthetic alkylphospholipid Akt inhibitor, using LNCaP and PC-3 prostate cancer cells. Perifosine treatment of PC-3 cells resulted in cytostatic and cytotoxic effects. Cytostatic effects were characterized by cell growth arrest, cell cycle block, and morphological changes, such as a cell enlargement and granulation, hallmarks of differentiating PC-3 cells. Specific differentiation markers including prostasomal, secretory and plasma membrane proteins, and keratins were induced by perifosine. Among them, we detected strong induction and secretion of CEACAM5 protein. In contrast, perifosine strongly reduced caveolin-1 RNA levels. Cytotoxic effects included para-apoptosis, apoptosis, and necrosis. To pursue the mechanisms responsible for these activities we focused on signaling pathways that lie downstream of Akt. Perifosine-triggered GSK-3beta activation in PC-3 and LNCaP cells resulted in the expression of GSK-3beta-related differentiation markers. This expression was reduced in the presence of specific siRNA for GSK-3beta or for its target CREB protein. The use of the GSK-3beta inhibitor lithium chloride indicated that GSK-3beta partially protects prostate cancer cells from the cytotoxic effects of perifosine. Together, these findings indicate that perifosine induces GSK-3beta-related differentiation and caspase-independent cell death in prostate cancer PC-3 cells. In addition our results identify specific biomarkers for perifosine therapy.
Floryk
Daniel
D
Scott Department of Urology, Baylor College of Medicine, Houston, TX 77030, USA. dfloryk@mdanderson.org
Thompson
Timothy C
TC
D021581:Active Transport, Cell Nucleus; D000728:Androgens / Q000502:physiology; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis; D015415:Biomarkers / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008297:Male; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics / Q000378:metabolism; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000633:toxicity; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000633:toxicity; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*
D000728:Androgens; D000970:Antineoplastic Agents; D015415:Biomarkers; D017362:Cyclic AMP Response Element-Binding Protein; D047428:Protein Kinase Inhibitors; D010767:Phosphorylcholine; C105905:perifosine; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3