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EGF/EGFR signaling axis is a significant regulator of the proteasome expression and activity in colon cancer cells

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      Abstract

      Colon cancer is the third most common type of cancer worldwide. Epidermal growth factor receptor (EGFR) plays a crucial role in the (patho)physiology of the disease. EGFR controls vital cellular processes, while this action is associated with poor prognosis. In addition, K-Ras mutations are associated with the promotion of the disease and the anti-EGFR resistance. The ubiquitin-proteasome system plays also a very important role in cancer, modulating cell cycle and other cellular processes such as the growth and the survival of cancer cells. Proteasome inhibition affects, in several cases, the action and the protein levels of EGFR. Nevertheless, little is known whether the reversed option is possible. In this study, we, therefore, investigated the impact of epidermal growth factor (EGF)/EGFR signaling axis on gene expression and the proteolytic activity of the proteasome subunits, as well as whether nuclear factor erythroid 2 related factor 2 (Nrf2), an activator of proteasome expression, plays a role in this process. Moreover, we evaluated whether EGF regulates the expression of its own receptor and the proliferation rate of DLD-1 (K-Ras mutated) colon cancer cells. The obtained data showed that, although EGF has no significant effect on the proliferation of DLD-1 colon cancer cells, it significantly upregulates the expression of EGFR as well as the expression and the activity of the proteasome, suggesting that the EGF-mediated proteasome activation could possibly lead to enhanced EGFR degradation leading to autoregulation of EGF–EGFR pathway. Nrf2 activation did not induce proteasome gene expression in DLD-1 colon cancer cells.

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      A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding

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        Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer.

        Panitumumab, a fully human antibody against the epidermal growth factor receptor (EGFR), has activity in a subset of patients with metastatic colorectal cancer (mCRC). Although activating mutations in KRAS, a small G-protein downstream of EGFR, correlate with poor response to anti-EGFR antibodies in mCRC, their role as a selection marker has not been established in randomized trials. KRAS mutations were detected using polymerase chain reaction on DNA from tumor sections collected in a phase III mCRC trial comparing panitumumab monotherapy to best supportive care (BSC). We tested whether the effect of panitumumab on progression-free survival (PFS) differed by KRAS status. KRAS status was ascertained in 427 (92%) of 463 patients (208 panitumumab, 219 BSC). KRAS mutations were found in 43% of patients. The treatment effect on PFS in the wild-type (WT) KRAS group (hazard ratio [HR], 0.45; 95% CI: 0.34 to 0.59) was significantly greater (P < .0001) than in the mutant group (HR, 0.99; 95% CI, 0.73 to 1.36). Median PFS in the WT KRAS group was 12.3 weeks for panitumumab and 7.3 weeks for BSC. Response rates to panitumumab were 17% and 0%, for the WT and mutant groups, respectively. WT KRAS patients had longer overall survival (HR, 0.67; 95% CI, 0.55 to 0.82; treatment arms combined). Consistent with longer exposure, more grade III treatment-related toxicities occurred in the WT KRAS group. No significant differences in toxicity were observed between the WT KRAS group and the overall population. Panitumumab monotherapy efficacy in mCRC is confined to patients with WT KRAS tumors. KRAS status should be considered in selecting patients with mCRC as candidates for panitumumab monotherapy.
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          Estimates of the cancer incidence and mortality in Europe in 2006.

          Monitoring the evolution of the cancer burden in Europe is of great value. Estimates of the cancer burden in Europe have been published for 2004 and estimates are now being presented for cancer incidence and mortality in Europe for 2006. The most recent sources of cancer incidence and mortality data have been collected and projections have been carried out using short-term prediction methods to produce estimated rates for 2006. Additional estimation was required where national incidence data were not available, and the method involved the projection of the aggregations of cancer incidence and mortality data from representative cancer registries. The estimated 2006 rates were applied to the corresponding estimated country population to obtain the best estimates of the cancer incidence and mortality in Europe in 2006. In 2006 in Europe, there were an estimated 3,191,600 cancer cases diagnosed (excluding nonmelanoma skin cancers) and 1,703,000 deaths from cancer. The most common form of cancers was breast cancer (429,900 cases, 13.5% of all cancer cases), followed by colorectal cancers (412,900, 12.9%) and lung cancer (386,300, 12.1%). Lung cancer, with an estimated 334,800 deaths (19.7% of total), was the most common cause of death from cancer, followed by colorectal (207,400 deaths), breast (131,900) and stomach (118,200) cancers. The total number of new cases of cancer in Europe appears to have increased by 300,000 since 2004. With an estimated 3.2 million new cases (53% occurring in men, 47% in women) and 1.7 million deaths (56% in men, 44% in women) each year, cancer remains an important public health problem in Europe and the ageing of the European population will cause these numbers to continue to increase even if age-specific rates remain constant. Evidence-based public health measures exist to reduce the mortality of breast and colorectal cancer while the incidence of lung cancer, and several other forms of cancer, could be diminished by improved tobacco control.
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            Author and article information

            Affiliations
            [1 ]Biochemistry, Biochemical Analysis and Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras, Greece
            [2 ]National Center of Scientific Research “Demokritos”, Institute of Biology, Laboratory of Cell Proliferation and Ageing, Athens, Greece
            Author notes
            [* ]Corresponding author's n.k.karamanos@ 123456upatras.gr address
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            Journal
            SOR-LIFE
            ScienceOpen Research
            ScienceOpen
            2199-1006
            14 May 2014
            : 0 (ID: 0003c012-d129-47a7-95ca-23a5647cd8e8 )
            : 0
            : 1-10
            3752:XE 10.14293/A2199-1006.01.SOR-LIFE.AC0E6.v1
            © 2014 Ellina et al.

            This work has been published open access under Creative Commons Attribution License CC BY 4.0 , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Conditions, terms of use and publishing policy can be found at www.scienceopen.com .

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            Figures: 6, Tables: 1, References: 60, Pages: 10
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