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

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The study is interesting and presents novel findings relevant for cancer therapy
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EGF/EGFR signaling axis is a significant regulator of the proteasome expression and activity in colon cancer cells

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 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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    Review text

    The study by Ellina et al reveals a novel role for EGF/EGFR signaling in the regulation of the proteasome in colon cancer cells. In order to address this, authors used end-point and RT-PCR for proteasome subunits genes, proteasome activity assay, cell proliferation assay together with the use of several pharmacological inhibitors.
    Thus by using tyrosine kinase inhibitors for the activation of EGFR and for its coreceptor, HER2, namely AG1478 and CP-724, 714, respectively, authors proved that EGF significantly increases the expression of β5, β1 and β2 proteasome subunits in an EGFR-dependent manner (as shown in Figure 3). This happens despite the presence of the K-Ras mutation which conferred cell proliferation resistance to the EGFR/HER2 inhibitors after EGF stimulation (as shown in Figure 2).
    Moreover by fluorescence measurements the study shows the involvement of EGF/EGFR pathway in the induction of the β5 catalytic proteasome activity (as shown in Figure 4). Authors might mention other degradation systems which might be regulated by the EGF/EGFR signaling and be involved in cancer cells proliferation and survival. At the same time it should be brought to discussion which degradation substrates and which type of ubiquitination are known to affect cancer cells in an EGF/EGFR signal-dependent manner.
    Authors excluded the influence of Nrf2 transcription factor on the EGF-mediated induced proteasome expression (as shown in Figure 5). However the authors might comment if there are any other transcription factors which can be involved in the proteasome expression and be regulated by the EGF/EGFR axis in cancer cells.
    Additionally, it was shown that the EGF/EGFR signaling increases the expression of EGFR itself and thus the proteasome activity might be amplified. Given that the canonical NF-kB activation requires the proteasomal degradation of IkBα it is worth discussing whether this transcription factor might be involved in the proteasome and EGFR expression. Here the study leaves room for further investigations concerning the feedback of the proteasome to degrade EGFR and consequently create an autoregulatory mechanism of EGF/EGFR pathway.

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