title: The overexpression of IGFBP-3 is involved in the chemosensitivity of esophageal squamous cell carcinoma cells to nimotuzumab combined with cisplatin.
abstract: Nimotuzumab is an antibody against epidermal growth factor receptor (EGFR). The objective of this study was to examine the capacity and specific underlying mechanisms of nimotuzumab to modulate cytotoxicity of cisplatin (DDP) in esophageal squamous cell carcinoma (ESCC) cell lines with different EGFR expression levels. Nimotuzumab was administrated to two ESCC cell lines KYSE30 and TE-1 treated with DDP. Cell growth, colony formation, and apoptosis were analyzed by MTT and flow cytometry assays. The method of RNA interference was used to investigate the role of insulin-like growth factor binding protein-3 (IGFBP-3) in ESCC cells chemosensitivity treated with nimotuzumab. Combination of nimotuzumab and DDP resulted in a DDP cytotoxicity increase in overexpressing EGFR cells (KYSE30) but not in low-expressing EGFR cells (TE-1). Meantime, DDP activated the EGFR pathway in the two cell lines in a ligand-independent fashion. Furthermore, DDP-induced EGFR activation was inhibited by nimotuzumab in KYSE30 cells, and this result was not observed in TE-1 cells. EGF reduced the expression of IGFBP-3 in KYSE30 cells; however, nimotuzumab could reverse the downregulation of IGFBP-3, and this result was also not observed in TE-1 cells. After IGFBP-3 was silenced by small interfering RNA, the potential of nimotuzumab to enhance DDP-mediated cytotoxicity was inhibited in KYSE30 cells. The results indicated that the increased ESCC chemosensitivity to DDP by nimotuzumab might be dependent on IGFBP-3 upregulation through EGFR-dependent pathway, which would facilitate preselection of ESCC patients for treatment of nimotuzumab combined with DDP.
authors.affiliation: Department of Radiotherapy, Cancer Center, Sun Yat-Sen University, No 651, Dongfeng Road East, Guangzhou 510060, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhao
authors.forename: Qiao-Qiao
authors.initials: QQ
authors.lastname: Li
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.forename: Mian
authors.initials: M
authors.lastname: Xi
authors.forename: Yi-Ji
authors.initials: YJ
authors.lastname: Liao
authors.forename: Dong
authors.initials: D
authors.lastname: Qian
authors.forename: Li-Ru
authors.initials: LR
authors.lastname: He
authors.forename: Yi-Xin
authors.initials: YX
authors.lastname: Zeng
authors.forename: Dan
authors.initials: D
authors.lastname: Xie
authors.forename: Meng-Zhong
authors.initials: MZ
authors.lastname: Liu
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D004938:Esophageal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D013997:Time Factors
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018972:Insulin-Like Growth Factor Binding Protein 3; C501466:nimotuzumab; C512478:EGFR protein, human; D066246:ErbB Receptors; D002945:Cisplatin