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Perifosine induces differentiation and cell death in prostate cancer cells.

ABSTRACT: 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.

SUBMITTER: Floryk D

PROVIDER: S-EPMC2525810 | biostudies-literature | 2008 Aug

REPOSITORIES: biostudies-literature

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Perifosine induces differentiation and cell death in prostate cancer cells.

Floryk Daniel D Thompson Timothy C TC

Cancer letters 20080418 2

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 pla ...[more]

PMID: 18395973

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Project description:We previously reported that marchantin M (Mar) is an active agent to induce apoptosis in human prostate cancer (PCa), but the molecular mechanisms of action remain largely unknown. Here, we demonstrate that Mar potently inhibited chymotrypsin-like and peptidyl-glutamyl peptide-hydrolyzing activities of 20S proteasome both in in vitro and intracellular systems and significantly induced the accumulation of polyubiquitinated proteins in PCa cells. The computational modeling analysis suggested that Mar non-covalently bound to active sites of proteasome ?5 and ?1 subunits, resulting in a non-competitive inhibition. Proteasome inhibition by Mar subsequently resulted in endoplasmic reticulum (ER) stress, as evidenced by elevated glucose-regulated protein 78 and CHOP, increased phospho-eukaryotic translation initiation factor 2? (eIF(2?)), splicing of X-box-binding protein-1 and dilation of the ER. However, Mar-mediated cell death was not completely impaired by a pan inhibitor of caspases. Further studies revealed that the Mar-induced cell death was greatly associated with the activation of autophagy, as indicated by the significant induction of microtubule-associated protein-1 light chain-3 beta (LC3B) expression and conversion. Electron microscopic and green fluorescent protein-tagged LC3B analyses further demonstrated the ability of autophagy induction by Mar. Time kinetic studies revealed that Mar induced a rapid and highly sustained processing of LC3B in treated cells and simultaneously decreased the expression of p62/SQSTM1. Pharmacological blockade or knockdown of LC3B and Atg5 attenuated Mar-mediated cell death. The autophagic response triggered by Mar required the activation of RNA-dependent protein kinase-like ER kinase/eIF(2?) and suppression of the phosphatidylinositol-3 kinase/Akt/mammalian target of rapamycin axis via preventing activation and expression of Akt. Our results identified a novel mechanism for the cytotoxic effect of Mar, which strengthens it as a potential agent in cancer chemotherapy.

Dataset Information

Perifosine induces differentiation and cell death in prostate cancer cells.

Publications

Perifosine induces differentiation and cell death in prostate cancer cells.

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