TY - JOUR

T1 - Multiple responses to EGF receptor activation and their abrogation by a specific EGF receptor tyrosine kinase inhibitor

AU - Harper, Maureen E.

AU - Goddard, Lindy

AU - Glynne-Jones, Eve

AU - Assender, Jean

AU - Dutkowski, Carol M.

AU - Barrow, Denise

AU - Dewhurst, Odette L.

AU - Wakeling, Alan E.

AU - Nicholson, Robert I.

N1 - Copyright 2002 Wiley-Liss, Inc.

PY - 2002/6/15

Y1 - 2002/6/15

N2 - BACKGROUND: Epidermal growth factor receptor (EGF-R) autophosphorylation is essential for its intracellular mitogenic signaling via the MAPK pathway and for interaction in other cellular processes. Inhibition of this activity in tumor cells that predominantly utilise EGF-R therefore offers an alternative approach to therapy.METHODS: The ability of a specific inhibitor of EGF-R tyrosine kinase, ZM 252868, (TKI) to alter various parameters related to growth in DU145 and PC3 cell lines was investigated, by immunocytochemistry, Northern blotting, Western blotting and invasion assays.RESULTS: In DU145 cultures, the total cell population and number of cells in cell cycle decreased in the presence of TKI whilst the apoptotic rate was significantly increased. Reduction in autophosphorylation of the EGF-R, membrane expression of EGF-R, activation of the MAPK, p38, and JNK enzymes and the invasive capacity of DU145 cells was observed in the TKI treated cells. Under the same conditions, PC3 cell growth and EGF-R expression and MAPK activation were not affected. The use of inhibitors of intracellular signaling indicated that the DU145 cells, in contrast to PC3 cells, predominantly utilize EGF-R activation of the MAPK signaling pathway for growth.CONCLUSIONS: In prostatic cancer patients, in whom androgen resistance has developed and whose tumors have upregulated EGF-R for growth, specific TKI's may offer an important therapy option.

AB - BACKGROUND: Epidermal growth factor receptor (EGF-R) autophosphorylation is essential for its intracellular mitogenic signaling via the MAPK pathway and for interaction in other cellular processes. Inhibition of this activity in tumor cells that predominantly utilise EGF-R therefore offers an alternative approach to therapy.METHODS: The ability of a specific inhibitor of EGF-R tyrosine kinase, ZM 252868, (TKI) to alter various parameters related to growth in DU145 and PC3 cell lines was investigated, by immunocytochemistry, Northern blotting, Western blotting and invasion assays.RESULTS: In DU145 cultures, the total cell population and number of cells in cell cycle decreased in the presence of TKI whilst the apoptotic rate was significantly increased. Reduction in autophosphorylation of the EGF-R, membrane expression of EGF-R, activation of the MAPK, p38, and JNK enzymes and the invasive capacity of DU145 cells was observed in the TKI treated cells. Under the same conditions, PC3 cell growth and EGF-R expression and MAPK activation were not affected. The use of inhibitors of intracellular signaling indicated that the DU145 cells, in contrast to PC3 cells, predominantly utilize EGF-R activation of the MAPK signaling pathway for growth.CONCLUSIONS: In prostatic cancer patients, in whom androgen resistance has developed and whose tumors have upregulated EGF-R for growth, specific TKI's may offer an important therapy option.

KW - Adenocarcinoma

KW - Apoptosis

KW - Blotting, Northern

KW - Blotting, Western

KW - Cell Count

KW - Cell Cycle

KW - Cell Division

KW - Enzyme Activation

KW - Enzyme Inhibitors

KW - Epidermal Growth Factor

KW - Humans

KW - Immunohistochemistry

KW - Male

KW - Mitogen-Activated Protein Kinases

KW - Neoplasm Invasiveness

KW - Phosphorylation

KW - Prostatic Neoplasms

KW - Quinazolines

KW - RNA, Messenger

KW - Receptor, Epidermal Growth Factor

KW - Signal Transduction

KW - Transforming Growth Factor alpha

KW - Tumor Cells, Cultured

U2 - 10.1002/pros.10069

DO - 10.1002/pros.10069

M3 - Journal article

C2 - 11992620

VL - 52

SP - 59

EP - 68

JO - The Prostate

JF - The Prostate

SN - 0270-4137

IS - 1

ER -