The cloning is described of two related human complementary DNAs encoding polypeptides that interact specifically with the translation initiation factor eIF-4E, which binds to the messenger RNA 5'-cap structure. Interaction of these proteins with eIF-4E inhibits translation but treatment of cells with insulin causes one of them to become hyperphosphorylated and dissociate from eIF-4E, thereby relieving the translational inhibition. The action of this new regulator of protein synthesis is therefore modulated by insulin, which acts to stimulate the overall rate of translation and promote cell growth.
"An important mechanism of 4E-BP regulation is through phosphorylation, which alters their ability to interact with eIF4E. Whereas hypophosphorylated 4E-BPs strongly associate with eIF4E, phosphorylation of the 4E-BPs on multiple residues weakens their interaction with eIF4E . High levels of phosphorylated 4E-BP1, which usually correlates with increased eIF4F assembly, were found in different malignancies, including breast, colorectal and prostate cancers  . "
"We found p-rpS6 levels to be attenuated only at the highest concentration of cetuximab. Furthermore, p-4E-BP1 levels were elevated at the lower concentration of cetuximab, suggesting increased potential for translation at the ribosomal cap . Taken together with the TK1 mRNA levels, these results may suggest that translational efficiency of TK1 at the lower level of cetuximab exposure that likely proceed through activation of mTOR. "
[Show abstract][Hide abstract] ABSTRACT: Biomarkers that predict response to targeted therapy in oncology are an essential component of personalized medicine. In preclinical treatment response studies that featured models of wild-type KRAS or mutant BRAF colorectal cancer treated with either cetuximab or vemurafenib, respectively, we illustrate that [18F]-FLT PET, a non-invasive molecular imaging readout of thymidine salvage, closely reflects pro-survival responses to targeted therapy that are mediated by PI3K-mTOR activity. Activation of pro-survival mechanisms forms the basis of numerous modes of resistance. Therefore, we conclude that [18F]-FLT PET may serve a novel and potentially critical role to predict tumors that exhibit molecular features that tend to reflect recalcitrance to MAPK-targeted therapy. Though these studies focused on colorectal cancer, we envision that the results may be applicable to other solid tumors as well.
PLoS ONE 09/2014; 9(9):e108193. DOI:10.1371/journal.pone.0108193 · 3.23 Impact Factor
"A previous study reported that, in response to IFN-α, the exponential growth of wild-type VHL RCC cells was inhibited more than that of VHL-null RCC cells. This observation indicated that VHL inactivation may be involved in IFN-α resistance and that combined immunotherapy with antiangiogenic drugs may be beneficial for patients with a mutated VHL gene (42,43). However, the effect of VHL activity on the synergy of IFN-α and RPM against RCC is unknown. "
[Show abstract][Hide abstract] ABSTRACT: The aim of the present study was to investigate the antiproliferative effects of interferon (IFN)-α and rapamycin (RPM) on renal cell carcinoma (RCC) cells and examine the synergistic growth suppression conferred by IFN-α and RPM. The effects of IFN-α and/or RPM on RCC cells were determined using a WST-1 assay and the synergy of IFN-α and RPM against three RCC cell lines was analyzed with isobolographic analysis. The expression of mammalian target of rapamycin (mTOR) was downregulated by RNAi, and the expression and phosphorylation of proteins in the mTOR pathway following treatment with IFN-α and/or RPM was examined by western blot analysis. The observations indicated that IFN-α significantly increased the susceptibility of RCC cells to RPM and the synergistic effect of IFN-α and RPM against RCC cells was confirmed in all three RCC cell lines. The mTOR pathway was shown to be associated with the synergistic effect of IFN-α and RPM against RCC. IFN-α and RPM alone decreased the phosphorylation of mTOR, p70 S6 kinase, S6 and 4E binding protein 1, and IFN-α significantly enhanced the RPM-induced suppression of the mTOR pathway. However, in RCC cells with low mTOR activity, the synergy of IFN-α and RPM was eliminated. Therefore, the results of the present study indicate that the mTOR pathway plays an important role in the synergistic effect of IFN-α and RPM against RCC cells. Thus, mTOR may serve as an effective therapeutic target in the treatment of advanced RCC.
Experimental and therapeutic medicine 07/2014; 8(1):267-273. DOI:10.3892/etm.2014.1691 · 1.27 Impact Factor
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