Raf-1 is the predominant Raf isoform that mediates growth factor-stimulated growth in ovarian cancer cells

Abstract

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.

Potentially important microRNA cluster on chromosome 17p13.1 in primary peritoneal carcinoma

“…Dysregulation of putative target genes within these lists have been described in ovarian cancer. [74][75][76][77][78][79][80][81][82][83][84][85][86][87][88] E-cadherin and acatenin, components of the cadherin pathway, have previously been found to be dysregulated in metatstatic ovarian carcinoma and serous effusions. [79][80][81] Polymorphisms in cyclin D2 and protein kinase C isoform expression have been linked with prognosis in ovarian carcinoma patients.…”

BRAFE600 in benign and malignant human tumours

“…Furthermore, inhibiting the entire RAF family would impact also on tumours with RAS mutations (CRAF being the preferred RAS effector; Dumaz et al, 2006) and tumours with CRAF overexpression (Figure 3). In fact, U0126 treatment or knockdown of CRAF, but not ARAF or BRAF, inhibits p-ERK as well as cell proliferation and induces apoptosis in ovarian cancer cell lines overexpressing CRAF (McPhillips et al, 2006). Although most experiments have been performed in vitro, the results suggest that an inhibitor targeting both BRAF E600 and wt BRAF, as well as ARAF and CRAF might be more effective and applicable to a broader range of tumours.…”

“…No ARAF mutations have been identified so far (Emuss et al, 2005;Lee et al, 2005). CRAF mutations are rarely found (Emuss et al, 2005;Zebisch et al, 2006), but the gene is overexpressed in some ovarian and pulmonary carcinomas, raising the possibility that also CRAF can act as an oncogene in man (Rapp et al, 1988;McPhillips et al, 2006).…”

Biomarkers for ovarian cancer detection and therapy

“…Additionally, b-Raf and c-Raf, two isoforms of Raf, are associated with ovarian cancer-high levels of b-Raf correlate with improved survival while high concentrations of c-Raf are associated with a poor prognosis. 107,108 Sorafenib is an oral, multi-kinase inhibitor that targets the MAPK pathway as well as VEGFR1-3 and PDGFR-β tyrosine kinase. It was initially combined with gemcitabine in a Phase II trial.…”