Ultraviolet Irradiation Can Induce Evasion of Colon Cancer Cells from Stimulation of Epidermal Growth Factor

Abstract

Receptor down-regulation is the most prominent regulatory system of EGF receptor (EGFR) signal attenuation and a critical target for therapy against colon cancer, which is highly dependent on the function of the EGFR. In this study, we investigated the effect of ultraviolet-C (UV-C) on down-regulation of EGFR in human colon cancer cells (SW480, HT29, and DLD-1). UV-C caused inhibition of cell survival and proliferation, concurrently inducing the decrease in cell surface EGFR and subsequently its degradation. UV-C, as well as EGFR kinase inhibitors, decreased the expression level of cyclin D1 and the phosphorylated level of retinoblastoma, indicating that EGFR down-regulation is correlated to cell cycle arrest. Although UV-C caused a marked phosphorylation of EGFR at Ser-1046/1047, UV-C also induced activation of p38 MAPK, a stress-inducible kinase believed to negatively regulate tumorigenesis, and the inhibition of p38 MAPK canceled EGFR phosphorylation at Ser-1046/1047, as well as subsequent internalization and degradation, suggesting that p38 MAPK mediates EGFR down-regulation by UV-C. In addition, phosphorylation of p38 MAPK induced by UV-C was mediated through transforming growth factor-␤-activated kinase-1. Moreover, pretreatment of the cells with UV-C suppressed EGF-induced phosphorylation of EGFR at tyrosine residues in addition to cell survival signal, Akt. Together, these results suggest that UV-C irradiation induces the removal of EGFRs from the cell surface that can protect colon cancer cells from oncogenic stimulation of EGF, resulting in cell cycle arrest. Hence, UV-C might be applied for clinical strategy against human colon cancers. Members of the EGF receptor (EGFR)2 family, which are frequently overexpressed in several types of human cancers, including cancers of the lung (1), head and neck (2), prostate (3), breast (4), pancreas (5), and colon (6), have been associated with abnormal growth of these tumors. It is well known that exposure of cells to EGF results in rapid autophosphorylation of EGFR molecules at the cell surface (7-10), which upon activation lead to cell proliferation, motility, and enhanced survival (11). There are several mechanisms by which EGFR becomes oncogenic including: 1) increased EGFR expression levels, 2) autocrine and/or paracrine growth factor loops, 3) heterodimerization with other EGFR family members and crosstalk with heterologous receptor systems, 4) defective receptor down-regulation, and 5) activating mutations (12). In clinical trials, increasing evidence shows the efficacy of EGFR-targeted agents, including monoclonal antibodies on the one hand and tyrosine kinase inhibitors on the other (13).Following activation, the ligand-receptor complexes are internalized and then enter endosomes, where the receptors and their ligands are sorted to various intracellular destinations (14). Thus, some receptors can be recycled back to the cell surface via early endosomes, and others are targeted to late endosomes and lysosomes for proteolytic degradation. There is increasin...

Modulating the Structure of EGFR with UV Light: New Possibilities in Cancer Therapy

“…Given the observed upregulation of p21WAF1 in our previous work [9], which is a cyclin dependent kinase inhibitor, we must assume that UV illumination causes the cells to arrest the cell cycle in G1 phase, which would be beneficial in inhibiting the proliferative potential of EGFR overexpressing cells. Adachi S. et al have also recently shown that UV irradiation can induce evasion of colon cancer cells from stimulation of epidermal growth factor [58]. They report that UV (254 nm) caused inhibition of cell survival and proliferation, concurrently inducing the decrease in cell surface EGFR and subsequently its degradation.…”

Epidermal growth factor/epidermal growth factor receptor signaling axis is a significant regulator of the proteasome expression and activity in colon cancer cells

“…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 EGFR in prostate cancer cells [45], our basic goal was to evaluate the effect of EGF/EGFR and then HER2 on the expression and the activity of the catalytic proteasome subunits. It is worth mentioning that in DLD-1 cancer cells, the introduction of exogenous EGF leads to phosphorylation of EGFR, as previously demonstrated [46]. As shown in Figure 1, EGF also significantly upregulated the expression of EGFR.…”

UVC irradiation suppresses platelet-derived growth factor-BB-induced migration in human pancreatic cancer cells

“…Similarly, we recently reported that UVC irradiation induces cell growth via downregulation of epidermal growth factor receptor (EGFR) (12) and also induces apoptosis (13) in human pancreatic cancer cells. Moreover, our recent study showed that UVC induced evasion of colon cancer cells from oncogenic stimulation by EGF (14). Hence, we believe that UVC could be applied for the clinical strategy against human malignancies including pancreatic cancer.…”