期刊
CANCER LETTERS
卷 266, 期 2, 页码 216-226出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2008.02.060
关键词
perifosine; prostate cancer; PC-3; LNCaP
类别
资金
- NCI NIH HHS [P50 CA058204-07S3, R01 CA050588-20, R01 CA050588-15, R01 CA068814-08, P50 CA058204-08S3, P50 CA058204-07S30005, P50 CA058204-060005, P50 CA058204-08S4, P50 CA058204, P50 CA058204-08S40005, P50 CA058204-08S1, P50 CA058204-08S30005, R01 CA050588-18A2, P50 CA058204-07S10005, R01 CA068814-09, R01 CA050588-17, P50 CA058204-08S5, R01 CA050588, R01 CA068814-11A1, R01 CA050588-16, P50 CA058204-07, P50 CA058204-08S10005, P50 CA058204-09, R01 CA050588-14, P50 CA058204-12S1, P50 CA058204-070005, R01 CA068814-06, P50 CA058204-10, P50 CA058204-08S20005, P50 CA058204-13, P50 CA058204-07S1, R01 CA068814, R01 CA050588-12, P50 CA058204-07S20005, R01 CA068814-13, P50 CA058204-11, P50 CA058204-08S6, P50 CA058204-080005, R01 CA068814-12, P50 CA058204-12, P50 CA058204-090013, P50 CA058204-08S50005, P50 CA058204-06S10005, R01 CA068814-10, P50 CA058204-11S1, P50 CA058204-07S2, P50 CA058204-090009, R01 CA050588-19, R01 CA050588-11, P50 CA058204-08S2, R01 CA050588-13, R01 CA068814-05, P50 CA058204-08, P50 CA058204-08S60005, R01 CA068814-07, P50 CA058204-050005] Funding Source: Medline
- PHS HHS [R01 68814] Funding Source: Medline
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-3 beta activation in PC-3 and LNCaP cells resulted in the expression of GSK-3 beta-related differentiation markers. This expression was reduced in the presence of specific siRNA for GSK-3 beta or for its target CREB protein. The use of the GSK-3 beta inhibitor lithium chloride indicated that GSK-3 beta partially protects prostate cancer cells from the cytotoxic effects of perifosine. Together, these findings indicate that perifosine induces GSK-3 beta-related differentiation and caspase-independent cell death in prostate cancer PC-3 cells. In addition our results identify specific biomarkers for perifosine therapy. Published by Elsevier Ltd.
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