ErbB1 and prostate cancer: ErbB1 activity is essential for androgen-induced proliferation and protection from the apoptotic effects of LY294002.
BACKGROUND
Androgens play a critical role in proliferation and survival of prostate cancer cells, but the mechanisms leading to these effects are poorly understood. ErbB receptor tyrosine kinases have been implicated in the development of prostate cancer.


METHODS
We examined the interaction between the ErbB receptors and androgens using the LNCaP androgen-sensitive prostate tumor model.


RESULTS
In the absence of androgens, the cells have low levels of ErbB1 and relatively high levels of ErbB2. Addition of androgens to the medium reversed the ratio; ErbB1 levels rose and ErbB2 levels dropped in response to treatment with the synthetic hormone, R1881. Expression of ErbB activating ligands was found to be constitutive and androgen-independent. The androgen-induced proliferation of LNCaP cells was completely inhibited by the addition of the small molecule ErbB1 tyrosine kinase inhibitors CGP59326 and the bispecific inhibitor (PKI166) for ErbB1 and ErbB2 to the culture medium. Furthermore, in the absence of androgens the relatively low proliferative level was further significantly reduced in the presence of CGP59326. Inhibition of PI3K activity by LY294002 led to induction of apoptosis in androgen-deprived LNCaP cells. Androgen-mediated rescue from LY294002-induced apoptosis was inhibited by addition of CGP59326 to the cells.


CONCLUSIONS
These results suggest a model whereby androgens promote an increase in the activity of the epidermal growth factor (EGF)-network by increasing ErbB1 levels, and this activity of is essential for androgen-induced proliferation and survival of the prostate cancer LNCaP cell line.
Tørring
Niels
N
Department of Clinical Biochemistry-AKH, Aarhus University Hospital, Aarhus C, Denmark. nto@sks.kba.au.dk
Dagnaes-Hansen
Frederik
F
Sørensen
Boe Sandahl
BS
Nexø
Ebba
E
Hynes
Nancy E
NE
D000728:Androgens / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008297:Male; D009025:Morpholines / Q000494:pharmacology*; D011471:Prostatic Neoplasms; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects
C111378:4-(phenylamino)-7H-pyrrolo(2,3-d)pyrimidine; D000728:Androgens; D002867:Chromones; D004791:Enzyme Inhibitors; D008024:Ligands; D009025:Morpholines; D011743:Pyrimidines; D011758:Pyrroles; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases