Relationship between the insulin-like growth factor 1 receptor signaling pathway and the resistance of nasopharyngeal carcinoma to cetuximab.
- Author:
Qiang ZUO
1
;
Rong-cheng LUO
Author Information
- Publication Type:Journal Article
- MeSH: ATP-Binding Cassette, Sub-Family B, Member 1; metabolism; Antibodies, Monoclonal; pharmacology; Antibodies, Monoclonal, Humanized; Antimetabolites, Antineoplastic; pharmacology; Antineoplastic Agents; pharmacology; Antineoplastic Agents, Phytogenic; pharmacology; Cell Cycle; drug effects; Cell Line, Tumor; Cell Proliferation; drug effects; Cetuximab; Cisplatin; pharmacology; Drug Resistance, Neoplasm; Fluorouracil; pharmacology; Humans; Nasopharyngeal Neoplasms; metabolism; pathology; Paclitaxel; pharmacology; Phosphorylation; Receptor, IGF Type 1; metabolism; Signal Transduction
- From: Chinese Journal of Oncology 2010;32(8):575-579
- CountryChina
- Language:Chinese
-
Abstract:
OBJECTIVETo establish a cetuximab-resistant human nasopharyngeal carcinoma 5-8F/Erbitux cell line and preliminarily study the relationship between the insulin-like growth factor 1 receptor (IGF-1R) signaling pathway and the resistance of nasopharyngeal carcinoma to cetuximab.
METHODSA nasopharyngeal cancer cell line, 5-8F, with high epidermal growth factor receptor (EGFR) expression and cetuximab sensitivity, was selected as study object. The cetuximab-resistant 5-8F/Erbitux cell line was induced by stepwise selection after exposure to increasing doses of cetuximab. The IC(50) was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and the resistance index (RI) was calculated. The growth curves of 5-8F and 5-8F/Erbitux cells were plotted and the doubling times were calculated by cell counting assay. The cell cycle was detected by flow cytometry. Cross-resistance profiles of 5-8F/Erbitux cells to 5-Fu, Taxol and DDP were tested by MTT assay. Expression levels of P-gP, IGF-1R and P-IGF-1R of 5-8F and 5-8F/Erbitux cells were determined by Western blot analysis and MDR1 gene by real-time fluorescent quantitative PCR.
RESULTSA cetuximab-resistant human nasopharyngeal carcinoma cell line 5-8F/Erbitux was successfully established and their resistance index (RI) were 1.2 and 1.1, respectively, at 3 d and 5 d of the cetuximab treatment. The doubling times of 5-8F and 5-8F/Erbitux cells were 26.63 h and 142.30 h, respectively. Flow cytometry demonstrated that 5-8F/Erbitux cells showed an increased population at G(0)/G(1) phase (P < 0.001) and reduced population at S phase (P < 0.001), compared with 5-8F cells. The 5-8F/Erbitux cells showed cross-resistance to 5-Fu (RI = 3.95, P < 0.01) and some resistance to Taxol as well as enhanced sensitivity to DDP (P > 0.05 for all). The 5-8F/Erbitux cells also had increased levels of P-gP, IGF-1R and P-IGF-1R compared with 5-8F cells (P < 0.001 for all). Expression of MDR1 gene was not detected in 5-8F cells and only very weak expression in 5-8F/Erbitux cells.
CONCLUSIONCetuximab-resistant 5-8F/Erbitux cells have no common multidrug resistance like that induced by traditional chemotherapeutic drugs. The excessive activation of the IGF-1R signaling pathway is probably one of the mechanisms that caused resistance of 5-8F/Erbitux cells to cetuximab.
