Basic fibroblast growth factor mediated growth inhibition in breast cancer cells is independent of ras signaling pathway.
Our previous studies have demonstrated that basic fibroblast growth factor (bFGF) inhibits the growth of MCF-7 human breast cancer cells via binding to high affinity cell surface receptors. The downstream signaling of bFGF was reported to involve the ras pathway. The aim of the present study was to examine the bFGF-induced growth inhibition in the presence of lovastatin, a farnesyl transferase inhibitor, which impaired ras signaling by preventing its association with the plasma membrane. We found that the combined cytotoxicity induced by lovastatin and bFGF was greater than the cytotoxicity induced by each agent alone. Similarly, the protein level of P21/WAF1/cip1 was greater after exposure to both agents together, than separately. bFGF did not interfere with the lovastatin-induced inhibition of P21/RAS membrane association, while lovastatin did not prevent MAPK activation by bFGF. Based on these findings we suggest that the growth inhibitory effect of bFGF on breast cancer cells is largely independent of the ras signaling pathway. Understanding these pathways may enable active intervention to alter the therapeutic ratio favorably in the treatment of breast cancer.
Fenig
Eyal
E
Institute of Oncology, Rabin Medical Center, Beilinson Campus, Petah Tiqva 49100, Israel. efenig@clalit.org.il
Szyper-Kravitz
Martin
M
Yerushalmi
Rinat
R
Lahav
Meir
M
Beery
Einat
E
Wasserman
Lina
L
Gutman
Haim
H
Nordenberg
Jardena
J
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004359:Drug Therapy, Combination; D051231:Farnesyltranstransferase; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D006801:Humans; D008148:Lovastatin / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D015689:Oncogene Protein p21(ras) / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000378:metabolism
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016222:Fibroblast Growth Factor 2; D008148:Lovastatin; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D015689:Oncogene Protein p21(ras)