title: Multiple responses to EGF receptor activation and their abrogation by a specific EGF receptor tyrosine kinase inhibitor.
abstract: 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.
authors: Tenovus Centre for Cancer Research, Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff, United Kingdom. HarperME1@Cardiff.ac.uk
authors: Maureen E
authors: ME
authors: Harper
authors: Lindy
authors: L
authors: Goddard
authors: Eve
authors: E
authors: Glynne-Jones
authors: Jean
authors: J
authors: Assender
authors: Carol M
authors: CM
authors: Dutkowski
authors: Denise
authors: D
authors: Barrow
authors: Odette L
authors: OL
authors: Dewhurst
authors: Alan E
authors: AE
authors: Wakeling
authors: Robert I
authors: RI
authors: Nicholson
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology*; D017209:Apoptosis; D015152:Blotting, Northern; D015153:Blotting, Western; D002452:Cell Count; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000473:pathology*; D011799:Quinazolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction; D016211:Transforming Growth Factor alpha / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D004791:Enzyme Inhibitors; D011799:Quinazolines; D012333:RNA, Messenger; D016211:Transforming Growth Factor alpha; C106485:ZM 252868; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases