Oncogenic Ras modulates epidermal growth factor responsiveness in endometrial carcinomas.
Since the majority of endometrial carcinomas do not contain any detectable ras mutations, the precise contribution of aberrant Ras function, if any, to endometrial carcinoma development remains to be determined. Since there is considerable evidence that Ras transformation is associated with a decreased requirement for growth factors, we compared the growth response of endometrial carcinoma cells harbouring wild-type (Ishikawa cells) or mutated (HHUA cells) K-ras to epidermal growth factor (EGF). K-ras mutation did not significantly affect the level of the EGF receptor (EGFR) expressed in these carcinoma cells. EGF could stimulate the growth of Ishikawa, but not HHUA cells. Furthermore, EGF caused elevation of Ras-GTP levels in Ishikawa, but not HHUA cells. However, the introduction of mutated, but not normal, K-ras into Ishikawa cells rendered them non-responsive to EGF growth stimulation. Thus, the presence of mutated K-ras alone modulated the growth response of endometrial carcinoma cells to EGF. An inhibitor of the EGFR tyrosine kinase activity could prevent soft agar colony formation of Ishikawa cells, but not HHUA or mutant K-ras(12V)-transfected Ishikawa cells. Taken together, these results suggest that mutated K-ras causes a loss of responsiveness to EGF stimulation and that EGFR function is dispensable for the growth of mutant Ras-positive endometrial carcinoma cells.
Department of Reproductive Physiology and Endocrinology, Kyushu University, Oita, Japan.
K
K
Kato
Y
Y
Ueoka
K
K
Kato
T
T
Tamura
J
J
Nishida
N
N
Wake
D017209:Apoptosis / Q000235:genetics; D002455:Cell Division; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000235:genetics* / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D011905:Genes, ras; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology; D009154:Mutation; D015398:Signal Transduction; D016211:Transforming Growth Factor alpha / Q000378:metabolism; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D006873:Hydroquinones; D016211:Transforming Growth Factor alpha; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; C048212:erbstatin