Raf-1 is the predominant Raf isoform that mediates growth factor-stimulated growth in ovarian cancer cells.
There is currently much interest in the role of the Raf family in cancer, particularly since mutated B-Raf has been shown to be oncogenic in certain disease types. In this study we have explored the expression, signaling and function of the three known Raf isoforms (Raf-1, A-Raf and B-Raf) in patients with ovarian cancer. While increased expression of Raf-1 was associated with poor survival, increased expression of B-Raf was associated with improved survival. Using a panel of ovarian cancer cell lines, all three isoforms were shown to be involved in growth factor initiated signaling. Antisense inhibition of function in ovarian cancer cell lines indicated that both Raf-1 and A-Raf, but not B-Raf, were linked to cell proliferation. Raf-1 (but not A-Raf or B-Raf) was also associated with reduced apoptosis. While individual Raf reduction by isoform-targeted antisense oligonucleotides (ODNs) produced growth inhibition in some cell lines, similar use of the MEK inhibitor UO126 produced growth inhibition in all cell lines tested. These data suggest that Raf-1 is the predominant Raf isoform responsible for regulating cellular growth in ovarian cancer cells and may be particularly important in high grade serous ovarian cancers.
McPhillips
Fiona
F
Cancer Research UK Centre, University of Edinburgh, Edinburgh EH4 2XR, UK.
Mullen
Peter
P
MacLeod
Kenneth G
KG
Sewell
Jane M
JM
Monia
Brett P
BP
Cameron
David A
DA
Smyth
John F
JF
Langdon
Simon P
SP
D049109:Cell Proliferation; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007527:Isoenzymes; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000473:pathology*; D011379:Prognosis; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D015398:Signal Transduction; D016019:Survival Analysis; D014407:Tumor Cells, Cultured
D007527:Isoenzymes; D016376:Oligonucleotides, Antisense; D019908:Proto-Oncogene Proteins c-raf