Abstract
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 also plays a very important role in cancer, modulating the 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 EGF/EGFR signaling axis on gene expression and the proteolytic activity of the proteasome subunits, as well as whether nuclear factor erythroid-derived 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 auto-regulation of EGF-EGFR pathway. Nrf2 activation did not induce proteasome gene expression.
Highlights
Colon cancer is estimated to be one of the most common types of cancer in Europe and the USA [1, 2]
Taking into consideration previous studies showing that EGF appears to regulate the survival time of Caenorhabditis elegans by activating proteasome [44] and that EGF increases proteasome expression through activation of Epidermal growth factor receptor (EGFR) in prostate cancer cells [45], our basic goal was to evaluate the effect of EGF/EGFR and HER2 on the expression and the activity of the catalytic proteasome subunits
It might be that EGF activates EGFR, which in turn enhances the expression and activation of proteasome that contributes to the activation of NF-κB pathway which mediates the upregulation of EGFR gene expression
Summary
Colon cancer is estimated to be one of the most common types of cancer in Europe and the USA [1, 2]. The dimerization of the receptor causes crossphosphorylation of its intracellular part and, the phosphorylated sites of the receptor act as docking sites for several signaling molecules, containing SH2 or PTB binding sites [8]. The activation of such molecules initiates specific signaling pathways, which in turn activate several transcription factors. EGFR mainly uses four signaling pathways: RasRaf-Mek-Erk, PI3K-Akt, Jak-Stat, and PLCγ-PKC. Another very important and well-studied receptor of the ErbB family is HER2/neu.
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