Blog
About

353
views
2
recommends
+1 Recommend
1 collections
    20
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

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

      This is not the latest version for this article. If you want to read the latest version, click here.

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          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.

          Related collections

          Most cited references 52

          • Record: found
          • Abstract: found
          • Article: not found

          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.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting.

            Matrix metalloproteinases (MMPs) consist of a multigene family of zinc-dependent extracellular matrix (ECM) remodeling endopeptidases implicated in pathological processes, such as carcinogenesis. In this regard, their activity plays a pivotal role in tumor growth and the multistep processes of invasion and metastasis, including proteolytic degradation of ECM, alteration of the cell-cell and cell-ECM interactions, migration and angiogenesis. The underlying premise of the current minireview is that MMPs are able to proteolytically process substrates in the extracellular milieu and, in so doing, promote tumor progression. However, certain members of the MMP family exert contradicting roles at different stages during cancer progression, depending among other factors on the tumor stage, tumor site, enzyme localization and substrate profile. MMPs are therefore amenable to therapeutic intervention by synthetic and natural inhibitors, providing perspectives for future studies. Multiple therapeutic agents, called matrix metalloproteinase inhibitors (MMPIs) have been developed to target MMPs, attempting to control their enzymatic activity. Even though clinical trials with these compounds do not show the expected results in most cases, the field of MMPIs is ongoing. This minireview critically evaluates the role of MMPs in relation to cancer progression, and highlights the challenges, as well as future prospects, for the design, development and efficacy of MMPIs. © 2010 The Authors Journal compilation © 2010 FEBS.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Structure of 20S proteasome from yeast at 2.4 A resolution.

              The crystal structure of the 20S proteasome from the yeast Saccharomyces cerevisiae shows that its 28 protein subunits are arranged as an (alpha1...alpha7, beta1...beta7)2 complex in four stacked rings and occupy unique locations. The interior of the particle, which harbours the active sites, is only accessible by some very narrow side entrances. The beta-type subunits are synthesized as proproteins before being proteolytically processed for assembly into the particle. The proforms of three of the seven different beta-type subunits, beta1/PRE3, beta2/PUP1 and beta5/PRE2, are cleaved between the threonine at position 1 and the last glycine of the pro-sequence, with release of the active-site residue Thr 1. These three beta-type subunits have inhibitor-binding sites, indicating that PRE2 has a chymotrypsin-like and a trypsin-like activity and that PRE3 has peptidylglutamyl peptide hydrolytic specificity. Other beta-type subunits are processed to an intermediate form, indicating that an additional nonspecific endopeptidase activity may exist which is important for peptide hydrolysis and for the generation of ligands for class I molecules of the major histocompatibility complex.
                Bookmark

                Author and article information

                Contributors
                (View ORCID Profile)
                (View ORCID Profile)
                (View ORCID Profile)
                (View ORCID Profile)
                (View ORCID Profile)
                Journal
                SOR-LIFE
                ScienceOpen Research
                ScienceOpen
                2199-1006
                14 May 2014
                : 0 (ID: 0003c012-d129-47a7-95ca-23a5647cd8e8 )
                : 0
                : 1-10
                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
                Article
                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 .

                Page count
                Figures: 6, Tables: 1, References: 60, Pages: 10
                Product
                Categories
                Original Article

                Comments

                Comment on this article