The epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 (Iressa) suppresses c-Src and Pak1 pathways and invasiveness of human cancer cells.
OBJECTIVE
Abnormalities in the expression and signaling pathways downstream of the epidermal growth factor receptor (EGFR) contribute to the progression, invasion, and maintenance of the malignant phenotype in human cancers, including those of the head and neck and breast. Accordingly, agents such as the EGFR tyrosine kinase inhibitor (EGFR-TKI) ZD1839 (Iressa) are promising, biologically based treatments that are in various stages of preclinical and clinical development. The process of tumor progression requires, among other steps, increased transformation, directional migration, and enhanced cell survival; this study explored the effect of ZD1839 on the stimulation of c-Src and p21-activated kinase 1 (Pak1), which are vital for transformation, directional motility, and cell survival of cancer cells.


METHODS
We examined the effect of ZD1839 on biochemical and functional assays indicative of directional motility and cell survival, using human head and neck squamous cancer cells and breast cancer cells.


RESULTS
ZD1839 effectively inhibited c-Src activation and Pak1 activity in exponentially growing cancer cells. In addition, ZD1839 suppressed EGF-induced stimulation of EGFR autophosphorylation on Y1086 and Grb2-binding Y1068 sites, c-Src phosphorylation on Y215, and Pak1 activity. ZD1839 also blocked EGF-induced cytoskeleton remodeling, redistribution of activated EGFR, and in vitro invasiveness of cancer cells.


CONCLUSIONS
These studies suggest that the EGFR-TKI ZD1839 may cause potent inhibition of the Pak1 and c-Src pathways and, therefore, have potential to affect the invasiveness of human cancer cells deregulated in these growth factor receptor pathways.
Yang
Zhibo
Z
Department of Molecular and Cellular Oncology, The University of Texas, M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Bagheri-Yarmand
Rozita
R
Wang
Rui-An
RA
Adam
Liana
L
Papadimitrakopoulou
Vali Vassiliki
VV
Clayman
Gary L
GL
El-Naggar
Adel
A
Lotan
Reuben
R
Barnes
Christopher J
CJ
Hong
Waun Ki
WK
Kumar
Rakesh
R
D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D000081247:CSK Tyrosine-Protein Kinase; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D002470:Cell Survival; D003599:Cytoskeleton / Q000378:metabolism; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D000077156:Gefitinib; D006258:Head and Neck Neoplasms / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008856:Microscopy, Fluorescence; D009361:Neoplasm Invasiveness; D010641:Phenotype; D010766:Phosphorylation; D011233:Precipitin Tests; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology*; D015398:Signal Transduction; D014162:Transfection; D016596:Vinculin / Q000378:metabolism; D054462:p21-Activated Kinases; D019061:src-Family Kinases
D000970:Antineoplastic Agents; D011799:Quinazolines; D016596:Vinculin; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; C515903:PAK1 protein, human; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; D000077156:Gefitinib