Cisplatin‑induced non‑canonical endocytosis of EGFR via p38 phosphorylation of the C‑terminal region containing Ser‑1015 in non‑small cell lung cancer cells

Tanaka, Tomohiro; Ozawa, Tatsuhiko; Oga, Eiji; Muraguchi, Atsushi; Sakurai, Hiroaki

doi:10.3892/ol.2018.8485

Cited by 9 publications

(11 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We confirmed that p38, a member of the MAPK cascade, is indeed activated during SOF treatment and translocated into the nucleus. Interestingly, the role of p38 in the regulation of EGFR in response to stress stimuli was shown by several groups [32,33,51]. However, we could demonstrate that the inhibition of p38 had no effect on the increased activation of EGFR observed during the exposure of cells to SOF, which excludes p38 as a driver of EGFR activation in this context.…”

Section: Discussionmentioning

confidence: 57%

Sofosbuvir Activates EGFR-Dependent Pathways in Hepatoma Cells with Implications for Liver-Related Pathological Processes

Bojkova

Westhaus

Costa

et al. 2020

Cells

View full text Add to dashboard Cite

Direct acting antivirals (DAAs) revolutionized the therapy of chronic hepatitis C infection. However, unexpected high recurrence rates of hepatocellular carcinoma (HCC) after DAA treatment became an issue in patients with advanced cirrhosis and fibrosis. In this study, we aimed to investigate an impact of DAA treatment on the molecular changes related to HCC development and progression in hepatoma cell lines and primary human hepatocytes. We found that treatment with sofosbuvir (SOF), a backbone of DAA therapy, caused an increase in EGFR expression and phosphorylation. As a result, enhanced translocation of EGFR into the nucleus and transactivation of factors associated with cell cycle progression, B-MYB and Cyclin D1, was detected. Serine/threonine kinase profiling identified additional pathways, especially the MAPK pathway, also activated during SOF treatment. Importantly, the blocking of EGFR kinase activity by erlotinib during SOF treatment prevented all downstream events. Altogether, our findings suggest that SOF may have an impact on pathological processes in the liver via the induction of EGFR signaling. Notably, zidovudine, another nucleoside analogue, exerted a similar cell phenotype, suggesting that the observed effects may be induced by additional members of this drug class.

show abstract

Section: Discussionmentioning

confidence: 57%

Sofosbuvir Activates EGFR-Dependent Pathways in Hepatoma Cells with Implications for Liver-Related Pathological Processes

Bojkova

Westhaus

Costa

et al. 2020

Cells

View full text Add to dashboard Cite

show abstract

“…We looked at RCP tyrosine phosphorylation as cisplatin has been shown to increase tyrosine phosphorylation EGFR in cancer cells 51 , but our p-tyrosine pulldowns did not show any tyrosine phosphorylation on RCP. Cisplatin has also been shown to regulate serine phosphorylation of EGFR, leading to internalisation of EGFR, which was independent of tyrosine phosphorylation 52 . Whether or not RCP is phosphorylated upon chemotherapeutic exposure remains to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

Mutant p53 promotes RCP-dependent chemoresistance coinciding with increased delivery of P-glycoprotein to the plasma membrane

et al. 2021

View full text Add to dashboard Cite

TP53 is the most frequently mutated gene in cancers. Mutations lead to loss of p53 expression or expression of a mutant protein. Mutant p53 proteins commonly lose wild-type function, but can also acquire novel functions in promoting metastasis and chemoresistance. Previously, we uncovered a role for Rab-coupling protein (RCP) in mutant p53-dependent invasion. RCP promotes endosomal recycling and signalling of integrins and receptor tyrosine kinases. In a screen to identify novel RCP-interacting proteins, we discovered P-glycoprotein (P-gp). Thus, we hypothesised that mutant p53 could promote chemoresistance through RCP-dependent recycling of P-gp. The interaction between RCP and P-gp was verified endogenously and loss of RCP or mutant p53 rendered cells more sensitive to cisplatin and etoposide. In mutant p53 cells we detected an RCP-dependent delivery of P-gp to the plasma membrane upon drug treatment and decreased retention of P-gp substrates. A co-localisation of P-gp and RCP was seen in mutant p53 cells, but not in p53-null cells upon chemotherapeutic exposure. In conclusion, mutant p53 expression enhanced co-localisation of P-gp and RCP to allow for rapid delivery of P-gp to the plasma membrane and increased resistance to chemotherapeutics.

show abstract

“…The transfected cells were then cultured under either normoxic or hypoxic conditions. Western blotting results showed that the protein expression levels of EGFR, in addition to the autophosphorylation of one of its most important residues, Tyr1068 (28,29), were shown to be significantly increased in the LV-mdig group compared with those in the LV-con group (P<0.05). These two aforementioned parameters were found to be significantly reduced in the LV-mdig-RNAi group compared with those in the LV-mdig-RNAi-con group (P<0.05; Figs.…”

Section: Mdig Promotes the Protein Expression Of Egfr And P-egfrmentioning

confidence: 95%

The mineral dust-induced gene, mdig, regulates angiogenesis and lymphangiogenesis in lung adenocarcinoma by modulating the expression of VEGF-A/C/D via EGFR and HIF-1α signaling

et al. 2021

View full text Add to dashboard Cite

Mineral dust-induced gene (mdig) is a novel lung cancer-related oncogene. The aim of this study was to explore the effects of mdig on angiogenesis and lymphangiogenesis by vascular endothelial growth factor (VEGF) in lung adenocarcinoma. mdig-overexpressing A549, H1299 and 293T cells, mdig-silenced A549, human umbilical vein endothelial cells (HUVECs) and human lymphatic endothelial cells (HLECs) were cultured under normoxic and hypoxic conditions. Protein expression levels of mdig, epidermal growth factor receptor (EGFR), phospho(p)-EGFR Tyr1068, hypoxia-inducible factor-1α (HIF-1α), VEGF-A/C/D and VEGF-R1/R2/R3 were assessed using western blotting. mRNA expression levels of mdig, EGFR and HIF-1α were measured using RT-qPCR. Tube formation and xenograft tumor experiments were performed to examine the mechanism of mdig in angiogenesis and lymphangiogenesis. Protein expression levels of EGFR, HIF-1α and VEGF-A/C/D were significantly upregulated in cells cultured under hypoxic conditions compared with those cultured under normoxic conditions, whereas the levels of mdig were decreased. Protein expression levels of EGFR, p-EGFR and VEGF-A/R1/R2 were significantly increased in the mdig-overexpressing cells, whereas the levels of HIF-1α and VEGF-C/D/R3 were decreased compared with those in control cells, all of which were reversed in mdig-silenced cells. Tumor volumes and density of angiogenesis in the mdig-overexpressing group were significantly increased compared with those in the control group, whereas the density of lymphangiogenesis was decreased. No tumors formed in the mdig-silenced group after 3 weeks of assessment in vivo. Protein expression levels of EGFR, p-EGFR, VEGF-A and angiogenesis density were significantly reduced in the mdig-overexpressing cells treated with an EGFR inhibitor, whereas the levels of HIF-1α, VEGF-C/D and the lymphangiogenesis density were significantly increased in mdig-overexpressing cells treated with a HIF-1α agonist. All changes in protein expression were reversed in EGFR agonist and HIF-1α inhibitor treated mdig-silenced cells. In conclusion, mdig is an oxygen-sensitive protein that promotes tumor growth and angiogenesis by activating the EGFR/p-EGFR/VEGF-A/VEGF-R1/R2 pathway and inhibits lymphangiogenesis by blocking the HIF-1α/VEGF-C/D/VEGF-R3 pathway.

show abstract

Cisplatin‑induced non‑canonical endocytosis of EGFR via p38 phosphorylation of the C‑terminal region containing Ser‑1015 in non‑small cell lung cancer cells

Cited by 9 publications

References 32 publications

Sofosbuvir Activates EGFR-Dependent Pathways in Hepatoma Cells with Implications for Liver-Related Pathological Processes

Sofosbuvir Activates EGFR-Dependent Pathways in Hepatoma Cells with Implications for Liver-Related Pathological Processes

Mutant p53 promotes RCP-dependent chemoresistance coinciding with increased delivery of P-glycoprotein to the plasma membrane

The mineral dust-induced gene, mdig, regulates angiogenesis and lymphangiogenesis in lung adenocarcinoma by modulating the expression of VEGF-A/C/D via EGFR and HIF-1α signaling

Contact Info

Product

Resources

About