Raf kinases: Function, regulation and role in human cancer

Leicht, Deborah T.; Balan, Vitaly; Kaplun, Alexander; Singh‐Gupta, Vinita; Kaplun, Ludmila; Dobson, Melissa; Tzivion, Guri

doi:10.1016/j.bbamcr.2007.05.001

Cited by 264 publications

(222 citation statements)

References 188 publications

(313 reference statements)

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“…Knockout of C-Raf in mice or in C-Raf-deficient cells can cause Fas-induced apoptosis (43,60). We observed that transfection of ODN-Raf led to a significant detachment of transfected cells and loss of viability as determined by an MTS assay.…”

Section: Discussionmentioning

confidence: 77%

A Short Hairpin DNA Analogous to miR-125b Inhibits C-Raf Expression, Proliferation, and Survival of Breast Cancer Cells

Hofmann

Heinrich

Radziwil

et al. 2009

Molecular Cancer Research

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The noncoding RNA miR-125b has been described to reduce ErbB2 protein expression as well as proliferation and migration of cancer cell lines. As additional target of miR-125b, we identified the c-raf-1 mRNA by sequence analysis. We designed a short hairpin-looped oligodeoxynucleotide (ODN) targeted to the same 3′ untranslated region of c-raf-1 mRNA as miR-125b. The fully complementary ODN antisense strand is linked to a second strand constituting a partially double-stranded structure of the ODN. Transfection of the c-raf-1-specific ODN (ODN-Raf) in a breast cancer cell line reduced the protein levels of C-Raf, ErbB2, and their downstream effector cyclin D1 similar to miR-125b. MiR-125b as well as ODN-Raf showed no effect on the c-raf-1 mRNA level in contrast to small interfering RNA. Unlike miR-125b, ODN-Raf induced a cytopathic effect. This may be explained by the structural properties of ODN-Raf, which can form G-tetrads. Thus, the short hairpin-looped ODN-Raf, targeting the same region of c-raf-1 as miR-125b, is a multifunctional molecule reducing the expression of oncoproteins and stimulating cell death. Both features may be useful to interfere with tumor growth. (Mol Cancer Res 2009;7(10):1635-44)

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Section: Discussionmentioning

confidence: 77%

A Short Hairpin DNA Analogous to miR-125b Inhibits C-Raf Expression, Proliferation, and Survival of Breast Cancer Cells

Hofmann

Heinrich

Radziwil

et al. 2009

Molecular Cancer Research

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“…The major BRAF functions are believed to be mediated by phosphorylation and thus activate the MAPK1, MAP2K1, and MAP2K2 pathways. 118,214 Mutations in BRAF have been shown to impair responsiveness to Figure 8 Alternative algorithm for molecular testing for patients with lung adenocarcinomas. Approximately 25% of lung adenocarcinomas harbor KRAS mutations, which predict non-response to EGFR TKI therapy.…”

Section: Braf Mutationmentioning

confidence: 99%

Molecular pathology of lung cancer: key to personalized medicine

et al. 2012

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The majority of lung adenocarcinoma patients with epidermal growth factor receptor-(EGFR) mutated or EML4-ALK rearrangement-positive tumors are sensitive to tyrosine kinase inhibitors. Both primary and acquired resistance in a significant number of those patients to these therapies remains a major clinical problem. The specific molecular mechanisms associated with tyrosine kinase inhibitor resistance are not fully understood. Clinicopathological observations suggest that molecular alterations involving so-called 'driver mutations' could be used as markers that aid in the selection of patients most likely to benefit from targeted therapies. In this review, we summarize recent developments involving the specific molecular mechanisms and markers that have been associated with primary and acquired resistance to EGFR-targeted therapy in lung adenocarcinomas. Understanding these mechanisms may provide new treatment avenues and improve current treatment algorithms.

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“…S4). Ras propagates incoming messages from membrane growth factor receptors (e.g., EGFR) to downstream proteins such as Raf at defined l d lipid microdomains in the plasma membrane (15,16). As such, its translocation to the cytoplasm greatly affected the proliferative Ras/MAPK signaling, which is frequently overactive in cancer cells and responsible for their loss of differentiation (17,18).…”

Section: Ohoa Inhibits the Egfr/ras/map Kinase And Pi3k/akt Pathways Inmentioning

confidence: 99%

2-Hydroxyoleate, a nontoxic membrane binding anticancer drug, induces glioma cell differentiation and autophagy

Terés

Lladó

Higuera

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

115

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Despite recent advances in the development of new cancer therapies, the treatment options for glioma remain limited, and the survival rate of patients has changed little over the past three decades. Here, we show that 2-hydroxyoleic acid (2OHOA) induces differentiation and autophagy of human glioma cells. Compared to the current reference drug for this condition, temozolomide (TMZ), 2OHOA combated glioma more efficiently and, unlike TMZ, tumor relapse was not observed following 2OHOA treatment. The novel mechanism of action of 2OHOA is associated with important changes in membrane-lipid composition, primarily a recovery of sphingomyelin (SM) levels, which is markedly low in glioma cells before treatment. Parallel to membrane-lipid regulation, treatment with 2OHOA induced a dramatic translocation of Ras from the membrane to the cytoplasm, which inhibited the MAP kinase pathway, reduced activity of the PI3K/Akt pathway, and downregulated Cyclin D-CDK4/6 proteins followed by hypophosphorylation of the retinoblastoma protein (RB). These regulatory effects were associated with induction of glioma cell differentiation into mature glial cells followed by autophagic cell death. Given its high efficacy, low toxicity, ease of oral administration, and good distribution to the brain, 2OHOA constitutes a new and potentially valuable therapeutic tool for glioma patients.fatty acids | sphingomyelin synthase | cancer drug target | glioma biomarker C ancer cells of undifferentiated phenotype (e.g., glioma) have a poor prognosis and limited treatment options. Primary brain tumors, of which glioma is the most common, are generally associated with very high rates of mortality (ca. 90%), being the median survival of patients about 1 y (1, 2). Chemotherapy provides only modest benefits to radiotherapy and surgery being the alkylating agent temozolomide (TMZ) the reference drug; however, tumor relapse is usually observed, and TMZ only increases the patients' life expectancy about 2.5 m (from 12.1 to 14.6 m: ref.3). The present study was designed to investigate the efficacy of 2OHOA against glioma and its molecular mechanisms of action. 2OHOA exhibited a greater efficacy than TMZ in the treatment of glioma, and there was no relapse after long-term treatment with 2OHOA. This efficacy and lack of toxicity at therapeutic doses has been acknowledged recently by the European Medicines Agency (EMA) to designate 2OHOA orphan drug for the treatment of glioma. In previous studies, we showed that this compound induces cell cycle arrest of lung cancer cells (4-6). Here, we showed that 2OHOA reversed the altered lipid profile of glioma cells and how this modification regulated cell signaling to induce autophagy specifically in glioma but not normal cells.Moreover, in the present study we demonstrated that the changes induced by 2OHOA were specific to cancer cells with no significant effects observed in normal cells and no adverse effects in treated animals, features not shared by most anticancer drugs. The efficacy of this compound in the absence ...

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Raf kinases: Function, regulation and role in human cancer

Cited by 264 publications

References 188 publications

A Short Hairpin DNA Analogous to miR-125b Inhibits C-Raf Expression, Proliferation, and Survival of Breast Cancer Cells

A Short Hairpin DNA Analogous to miR-125b Inhibits C-Raf Expression, Proliferation, and Survival of Breast Cancer Cells

Molecular pathology of lung cancer: key to personalized medicine

2-Hydroxyoleate, a nontoxic membrane binding anticancer drug, induces glioma cell differentiation and autophagy

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