title: Epidermal growth factor protects squamous cell carcinoma against cisplatin-induced cytotoxicity through increased interleukin-1β expression.
abstract: 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 examined the transcriptional activity and mRNA stability of IL-1β in EGF-treated cells. We found that EGF induced the expression of IL-1β and was mediated through transcriptional activation, but not through mRNA stability. The involvement of Akt and NF-κB signaling pathways in the EGF-induced IL-1β gene expression was confirmed by knockdown of RelA and Akt in cells or treating cells with Akt and NF-κB inhibitors, LY294002 and parthenolide, respectively. The expression of dominant negative IκB also repressed the activation of NF-κB and inhibited EGF-induced IL-1β expression. Using immunofluorescence staining assay, the EGF-stimulated nuclear translocation of NF-κB (p65) was inhibited by pre-treating cells with LY294002 and parthenolide. Furthermore, EGF increased the binding of NF-κB to the NF-κB binding site of the IL-1β promoter through the activation of the Akt/NF-κB pathway, which resulted in activating IL-1β promoter activity. The expression and secretion of IL-1β induced by EGF considerably reduced chemotherapeutic drug cisplatin-induced cell death. These results showed that EGF enhanced the expression of IL-1β, which was mediated by the Akt/NF-κB pathway. The activation of EGF signaling and increase of IL-1β contributed to chemotherapeutic resistance of cancer cells, suggesting that the expression of IL-1β may be used as a biomarker to evaluate successful cancer treatment.
authors: Department of Chest Medicine, Chi Mei Medical Center, Tainan, Taiwan, Republic of China.
authors: Shian-Chin
authors: SC
authors: Ko
authors: Chi-Ruei
authors: CR
authors: Huang
authors: Jiunn-Min
authors: JM
authors: Shieh
authors: Jhen-Hong
authors: JH
authors: Yang
authors: Wen-Chang
authors: WC
authors: Chang
authors: Ben-Kuen
authors: BK
authors: Chen
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism*; D002867:Chromones; D002945:Cisplatin / Q000378:metabolism / Q000494:pharmacology*; D003603:Cytotoxins / Q000378:metabolism / Q000494:pharmacology*; D017931:DNA Primers / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism*; D009025:Morpholines; D016328:NF-kappa B / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012717:Sesquiterpenes; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
chemical_list: D014408:Biomarkers, Tumor; D002867:Chromones; D003603:Cytotoxins; D017931:DNA Primers; D053583:Interleukin-1beta; D009025:Morpholines; D016328:NF-kappa B; D034741:RNA, Small Interfering; D012717:Sesquiterpenes; C002669:parthenolide; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D051058:Oncogene Protein v-akt; D002945:Cisplatin
references: J Clin Invest. 2005 Nov;115(11):2979-91
references: 16239969
references: Blood. 1998 Jan 15;91(2):577-84
references: 9427712
references: Br J Cancer. 2009 Jan 13;100(1):134-44
references: 19088723
references: Cytokine. 1999 Sep;11(9):689-95
references: 10479405
references: Clin Cancer Res. 2009 Dec 1;15(23):7389-97
references: 19920104
references: Genes Dev. 2006 Nov 15;20(22):3174-84
references: 17085481
references: J Biol Chem. 2003 May 30;278(22):20077-82
references: 12637573
references: Nat Rev Mol Cell Biol. 2007 Jan;8(1):49-62
references: 17183360
references: Br J Pharmacol. 2000 Sep;131(1):152-9
references: 10960082
references: Cancer Res. 1993 Aug 1;53(15):3579-84
references: 8339264
references: J Biol Chem. 2010 Feb 26;285(9):6477-88
references: 20038581
references: Sci Signal. 2010 Jan 19;3(105):cm1
references: 20086235
references: Eur J Cancer. 2001 Sep;37 Suppl 4:S9-15
references: 11597399
references: J Clin Invest. 2007 May;117(5):1155-66
references: 17476345
references: Cancer Metastasis Rev. 2006 Sep;25(3):387-408
references: 17043764
references: Mol Pharmacol. 2002 May;61(5):953-63
references: 11961112
references: Cancer Res. 2010 Apr 1;70(7):2862-9
references: 20215522
references: Endocr Relat Cancer. 2001 Mar;8(1):11-31
references: 11350724
references: Immunol Rev. 2008 Apr;222:180-91
references: 18364002
references: Nat Rev Immunol. 2009 Mar;9(3):162-74
references: 19197294
references: Adv Exp Med Biol. 2000;479:277-88
references: 10897428
references: Cancer Res. 1999 Sep 15;59(18):4551-4
references: 10493505
references: J Pharmacol Exp Ther. 1994 Sep;270(3):1313-8
references: 7932184
references: Gene. 2006 Jan 17;366(1):2-16
references: 16377102
references: Cancer Chemother Pharmacol. 2001 May;47(5):397-403
references: 11391854
references: Int J Oncol. 2003 Aug;23(2):269-84
references: 12851675
references: Nat Immunol. 2009 Mar;10(3):241-7
references: 19221555
references: Nucleic Acids Res. 1991 May 11;19(9):2499
references: 2041787
references: Life Sci. 1999;65(5):449-81
references: 10462074
references: J Immunol. 2005 Dec 15;175(12):8200-8
references: 16339559
references: Mol Cell Biol. 1993 Oct;13(10):6231-40
references: 8413223
references: J Biol Chem. 2009 Apr 10;284(15):9908-16
references: 19203995
references: J Exp Med. 1991 Nov 1;174(5):1147-57
references: 1940795
references: Crit Rev Oncol Hematol. 1995 Jul;19(3):183-232
references: 7612182
references: Clin Exp Rheumatol. 2007 Nov-Dec;25(6):831-7
references: 18173916
references: Biochem J. 1997 May 15;324 ( Pt 1):133-40
references: 9164849
references: Biochem Pharmacol. 2006 Oct 30;72(9):1102-13
references: 16930560
references: Expert Opin Ther Targets. 2007 Jul;11(7):869-80
references: 17614756
references: Cytokine. 2000 Jun;12(6):547-54
references: 10843728
references: J Biol Chem. 2002 Mar 1;277(9):6923-8
references: 11741938
references: Cancer Invest. 2000;18(4):293-302
references: 10808364
references: FASEB J. 2003 Nov;17(14):2115-7
references: 12958148
references: Cancer Res. 2003 Jun 1;63(11):2948-56
references: 12782602
references: J Immunol. 1986 Apr 1;136(7):2483-5
references: 3512714
references: J Exp Med. 2005 May 2;201(9):1355-9
references: 15867089
references: Clin Microbiol Rev. 2002 Jul;15(3):414-29
references: 12097249
references: Int J Cancer. 2002 Jun 1;99(4):538-48
references: 11992543
references: Stem Cells Dev. 2012 Sep 1;21(13):2541-51
references: 22316125
references: Cancer. 1996 Sep 15;78(6):1284-92
references: 8826952
references: J Immunol. 2003 Dec 15;171(12):6448-56
references: 14662844
references: Clin Cancer Res. 2011 Nov 15;17(22):7116-26
references: 21976531