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Epidermal growth factor protects squamous cell carcinoma against cisplatin-induced cytotoxicity through increased interleukin-1? expression.

ABSTRACT: The expression of cytokines, such as IL-1?, and the activation of the epidermal growth factor receptor (EGFR) are crucial regulators in the process of carcinogenesis. The correlation between growth factor and activated cytokine signals in the control of tumor development is a critical issue to be clarified. In our study, we found that the IL-1? gene and protein expression were induced by EGF in squamous cell carcinoma. To clarify the mechanism involved in EGF-regulated IL-1? expression, we examined the transcriptional activity and mRNA stability of IL-1? in EGF-treated cells. We found that EGF induced the expression of IL-1? and was mediated through transcriptional activation, but not through mRNA stability. The involvement of Akt and NF-?B signaling pathways in the EGF-induced IL-1? gene expression was confirmed by knockdown of RelA and Akt in cells or treating cells with Akt and NF-?B inhibitors, LY294002 and parthenolide, respectively. The expression of dominant negative I?B also repressed the activation of NF-?B and inhibited EGF-induced IL-1? expression. Using immunofluorescence staining assay, the EGF-stimulated nuclear translocation of NF-?B (p65) was inhibited by pre-treating cells with LY294002 and parthenolide. Furthermore, EGF increased the binding of NF-?B to the NF-?B binding site of the IL-1? promoter through the activation of the Akt/NF-?B pathway, which resulted in activating IL-1? promoter activity. The expression and secretion of IL-1? induced by EGF considerably reduced chemotherapeutic drug cisplatin-induced cell death. These results showed that EGF enhanced the expression of IL-1?, which was mediated by the Akt/NF-?B pathway. The activation of EGF signaling and increase of IL-1? contributed to chemotherapeutic resistance of cancer cells, suggesting that the expression of IL-1? may be used as a biomarker to evaluate successful cancer treatment.

SUBMITTER: Ko SC

PROVIDER: S-EPMC3562190 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Epidermal growth factor protects squamous cell carcinoma against cisplatin-induced cytotoxicity through increased interleukin-1β expression.

Ko Shian-Chin SC Huang Chi-Ruei CR Shieh Jiunn-Min JM Yang Jhen-Hong JH Chang Wen-Chang WC Chen Ben-Kuen BK

PloS one 20130201 2

The expression of cytokines, such as IL-1β, and the activation of the epidermal growth factor receptor (EGFR) are crucial regulators in the process of carcinogenesis. The correlation between growth factor and activated cytokine signals in the control of tumor development is a critical issue to be clarified. In our study, we found that the IL-1β gene and protein expression were induced by EGF in squamous cell carcinoma. To clarify the mechanism involved in EGF-regulated IL-1β expression, we exami ...[more]

PMID: 23383347

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Project description:Cisplatin and its analogues are the most commonly used agents in the treatment of head and neck squamous cell carcinoma. In this study, we investigated a possible role of epidermal growth factor (EGF) receptor (EGFR) phosphorylation and degradation in cisplatin-induced cytotoxicity. Cisplatin treatment led to an increase in initial EGFR phosphorylation at Y1045, the binding site of ubiquitin ligase, Casitas B-lineage lymphoma (c-Cbl), followed by ubiquitination in the relatively cisplatin-sensitive cell lines. However, cisplatin-resistant cell lines underwent minimal EGFR phosphorylation at the Y1045 site and minimal ubiquitination. We found that EGFR degradation in response to cisplatin was highly correlated with cytotoxicity in seven head and neck cancer cell lines. Pretreatment with EGF enhanced cisplatin-induced EGFR degradation and cytotoxicity, whereas erlotinib pretreatment blocked EGFR phosphorylation, degradation, and cisplatin-induced cytotoxicity. Expression of a mutant Y1045F EGFR, which is relatively resistant to c-Cbl-mediated degradation, in Chinese hamster ovary cells and the UMSCC11B human head and neck cancer cell line protected EGFR from cisplatin-induced degradation and enhanced cell survival compared with wild-type (WT) EGFR. Transfection of WT c-Cbl enhanced EGFR degradation and cisplatin-induced cytotoxicity compared with control vector. These results show that cisplatin-induced EGFR phosphorylation and subsequent ubiquitination and degradation is an important determinant of cisplatin sensitivity. Our findings suggest that treatment with an EGFR inhibitor before cisplatin would be antagonistic, as EGFR inhibition would protect EGFR from cisplatin-mediated phosphorylation and subsequent ubiquitination and degradation, which may explain the negative results of several recent clinical trials. Furthermore, they suggest that EGFR degradation is worth exploring as an early biomarker of response and as a target to improve outcome.

Dataset Information

Epidermal growth factor protects squamous cell carcinoma against cisplatin-induced cytotoxicity through increased interleukin-1? expression.

Publications

Epidermal growth factor protects squamous cell carcinoma against cisplatin-induced cytotoxicity through increased interleukin-1β expression.

Similar Datasets

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