کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2114754 1084554 2008 11 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Perifosine induces differentiation and cell death in prostate cancer cells
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی تحقیقات سرطان
پیش نمایش صفحه اول مقاله
Perifosine induces differentiation and cell death in prostate cancer cells
چکیده انگلیسی

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-3β activation in PC-3 and LNCaP cells resulted in the expression of GSK-3β-related differentiation markers. This expression was reduced in the presence of specific siRNA for GSK-3β or for its target CREB protein. The use of the GSK-3β inhibitor lithium chloride indicated that GSK-3β partially protects prostate cancer cells from the cytotoxic effects of perifosine. Together, these findings indicate that perifosine induces GSK-3β-related differentiation and caspase-independent cell death in prostate cancer PC-3 cells. In addition our results identify specific biomarkers for perifosine therapy.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Cancer Letters - Volume 266, Issue 2, 8 August 2008, Pages 216–226
نویسندگان
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