In Silico Simulation of Epidermal Growth Factor Signaling in Prostate Cancer Cells

Neuroendocrine differentiation (NED) has been implicated in prostate cancer progression and hormone-therapy failure. Neuroendocrine cells are non-proliferating and escape apoptotic cell death, although their origin and the causes of their apoptotic resistance have as yet been poorly elucidated. This study demonstrates a new mechanism involved in controlling NED. We report that epidermal growth factor (5–50 ng/ml) promotes neuroendocrine-like differentiation of androgen-independent DU145 prostate cancer cells. This differentiation is associated with an increase in the expression of Neuron Specific Enolase (NSE) and a reduction in cell proliferation and is blocked by inhibiting tyrosine kinase activity with genistein and with compound 56 (C56). An increase in the cAMP level, using dibutryl cAMP (db-cAMP) (1 mM) and isobutylmethylxanthine (100 μM), does not promote NED by itself, but does increase the effect of EGF on NED. In addition, EGF-induced NED protects cells from apoptosis induced with thapsigargin (1 μM) by reducing the thapsigargin-induced cytosolic calcium overload. In order to describe how EGF-induced NED protects cells against thapigargin-induced calcium overload we investigated the spatiotemporal calcium signalling linked to apoptosis. By using thapsigargin in various conditions on DU145 cells and using micro-fluorimetric calcium measurements, we show that depletion of intracellular calcium store induces apoptosis and that the amplitude and duration of the capacitive calcium entry are two apoptosis-modulating parameters. We show that protection against thapsigargin-induced apoptosis conferred by NED is achieved by reducing the amount and the speed of calcium that can be released from calcium pools, as well as modulating the amplitude of the subsequent calcium entry.

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Critical role of acylglycerol kinase in epidermal growth factor-induced mitogenesis of prostate cancer cells

Biochemical Society Transactions ◽

10.1042/bst0331362 ◽

2005 ◽

Vol 33 (6) ◽

pp. 1362-1365 ◽

Cited By ~ 9

Author(s):

S. Spiegel ◽

S. Milstien

Keyword(s):

Prostate Cancer ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Cancer Cells ◽

Cannabinoid Receptor ◽

Critical Role ◽

Prostate Cancer Cells ◽

Lipid Kinase ◽

Epidermal Growth ◽

Acylglycerol Kinase

The bioactive phospholipids, LPA (lysophosphatidic acid) and PA (phosphatidic acid), regulate pivotal processes related to the pathogenesis of cancer. Recently, we cloned a novel type of lipid kinase that phosphorylates monoacylglycerols (such as 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand) and diacylglycerols, to form LPA and PA, respectively. This AGK (acylglycerol kinase) is highly expressed in prostate cancer cell lines and the results reviewed here suggest that AGK might be a critical player in the initiation and progression of prostate cancer. Intriguingly, down-regulation of endogenous AGK inhibited EGF (epidermal growth factor), but not LPA-induced ERK1/2 (extracellular-signal-regulated kinase 1/2) activation and progression through the S-phase of the cell cycle. In this review, we will summarize the evidence demonstrating that AGK amplifies EGF growth signalling pathways that play an important role in the pathophysiology of prostate cancer. Because LPA has long been implicated as an autocrine and paracrine growth stimulatory factor for prostate cancer cells, the identification of this novel lipid kinase that regulates its production could provide new and useful targets for preventive or therapeutic measures.

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