Phosphorylation of both EGFR and ErbB2 is a reliable predictor of prostate cancer cell proliferation in response to EGF.
Despite multiple reports of overexpression in prostate cancer (PC), the reliance of PC cells on activated epidermal growth factor receptor (EGFR) and its downstream signaling to phosphoinositide 3'-kinase/Akt (PI3K/Akt/PTEN) and/or mitogen-activated protein kinase (MAPK/ERK) pathways has not been fully elucidated. In this study, we compared the role of EGF-mediated signaling in nonmalignant (BPH-1, PNT1A, and PNT1B) and PC cell lines (DU145, PC3, LNCaP, and CWR22Rv1). EGF-induced proliferation was observed in all EGFR-expressing PC cells except PC3, indicating that EGFR expression does not unequivocally trigger proliferation following EGF stimulation. ErbB2 recruitment potentiated EGF-induced signals and was associated with the most pronounced effects of EGF despite low EGFR expression. In this way, the sum of EGFR and ErbB2 receptor phosphorylation proved to be a more sensitive indicator of EGF-induced proliferation than quantification of the expression of either receptor alone. Both Akt and ERK were rapidly phosphorylated in response to EGF, with ERK phosphorylation being the weakest in PC3 cells. Extrapolation of these findings to clinical PC suggests that assessment of phosphorylated EGFR + ErbB2 together could serve as a marker for sensitivity to anti-EGFR-targeted therapies.
El Sheikh
Soha Salama
SS
Department of Histopathology, Imperial College, Hammersmith Hospital Campus, Ducane Road, London W12 0NN, UK.
Domin
Jan
J
Abel
Paul
P
Stamp
Gordon
G
Lalani
El-Nasir
el-N
D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004789:Enzyme Activation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000187:drug effects / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*
D004791:Enzyme Inhibitors; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D020929:Mitogen-Activated Protein Kinase Kinases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; C494918:AKT1 protein, human
Cancer Lett. 1998 Dec 25;134(2):177-80
10025878
Oncogene. 1997 Nov 27;15(22):2705-16
9400997
Prostate. 1997 Feb 15;30(3):195-201
9122045
Exp Cell Res. 1999 Nov 25;253(1):239-54
10579926
Cancer Res. 1998 Jul 1;58(13):2720-3
9661880
Urology. 2001 Aug;58(2 Suppl 1):114-22
11502465
Cancer Res. 1991 Jun 1;51(11):2780-5
2032218
BJU Int. 2000 May;85(7):932-44
10792179
Cell. 1986 Jun 6;45(5):649-57
2871941
Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1746-50
8383326
Cancer. 2002 Jun 15;94(12):3127-34
12115344
Am J Pathol. 2002 Jan;160(1):339-45
11786427
In Vitro Cell Dev Biol Anim. 1999 Jul-Aug;35(7):403-9
10462204
Prostate. 1991;19(2):173-80
1923964
J Immunol. 2002 Nov 15;169(10):5441-50
12421919
Clin Cancer Res. 2003 Oct 1;9(12):4340-6
14555504
Science. 1997 Mar 28;275(5308):1943-7
9072974
Urology. 2002 Sep;60(3 Suppl 1):115-21; discussion 122
12231066
Cancer Metastasis Rev. 2003 Dec;22(4):395-403
12884914
Int J Cancer. 1995 Sep 15;62(6):724-31
7558421
J Urol. 1999 Oct;162(4):1537-42
10492251
Proc Natl Acad Sci U S A. 1999 Apr 13;96(8):4240-5
10200246
Int J Cancer. 2002 May 1;99(1):100-5
11948499
Semin Cancer Biol. 1994 Aug;5(4):261-8
7803762
Invest Urol. 1979 Jul;17(1):16-23
447482
Cancer Res. 2001 Nov 15;61(22):8135-42
11719442
Cell. 1994 Jul 15;78(1):5-8
8033211
Mol Cell Biol. 2000 Sep;20(18):6860-71
10958682
Histol Histopathol. 1999 Oct;14(4):1175-82
10506934
Biochem J. 2001 Dec 1;360(Pt 2):277-83
11716755
Int J Cancer. 1978 Mar 15;21(3):274-81
631930
Prog Clin Biol Res. 1980;37:115-32
7384082
J Biol Chem. 2000 Apr 21;275(16):11943-50
10766823
Proc Natl Acad Sci U S A. 1989 Dec;86(23):9193-7
2687875
Mol Cell Biol. 2000 Jun;20(11):3817-30
10805725
Cancer Res. 1999 Jan 1;59(1):227-33
9892211
Cytokine. 1999 Sep;11(9):722-7
10479409
J Urol. 1991 Sep;146(3):881-6
1714974
EMBO J. 1994 Jun 15;13(12):2831-41
8026468
Br J Cancer. 1990 Oct;62(4):579-84
2223575
Genes Dev. 1999 Nov 15;13(22):2905-27
10579998
In Vitro Cell Dev Biol Anim. 1995 Jan;31(1):14-24
7535634
Int Urol Nephrol. 1999;31(1):61-73
10408305
Mol Cell Biol. 2001 Oct;21(19):6660-7
11533253