Abstract
BackgroundLaryngeal cancer tends to have a very poor prognosis due to the unsatisfactory efficacy of chemotherapy for this cancer. Multidrug resistance (MDR) is the main cause of chemotherapy failure. The proto-oncogene c-fos has been shown to be involved in the development of MDR in several tumor types, but few studies have evaluated the relationship between c-fos and MDR in laryngeal cancer. We investigated the role of c-fos in MDR development in laryngeal cancer cells (cell line: human epithelial type 2, HEp-2) using the chemotherapeutic vincristine (VCR).MethodsHEp-2/VCR drug resistance was established by selection against an increasing drug concentration gradient. The expressions of c-fos and multidrug resistance 1 (mdr1) were measured using qPCR and western blot. C-fos overexpression or knockdown was performed in various cells. The intracellular rhodamine-123 (Rh-123) accumulation assay was used to detect the transport capacity of P-glycoprotein (P-gp, which is encoded by the mdr1 gene).ResultsHEp-2 cells with VCR-induced resistance (HEp-2/VCR cells) were not only resistant to VCR but also evolved cross-resistance to other chemotherapeutic drugs. The expressions of the c-fos and mdr1genes were significantly higher in the HEp-2/VCR cells than in control cells. C-fos overexpression in HEp-2 cells (c-fos WT) resulted in increased P-gp expression and increased the IC50 for 5-FU. C-fos knockdown in the HEp-2/VCR cells (c-fos shRNA) resulted in decreased P-gp expression and decreased IC50 for 5-FU. An intracellular Rh-123 accumulation assay showed that the mean intracellular fluorescence intensity (MFI) was lower in the HEp-2/VCR cells than in HEp-2 cells. C-fos WT cells also showed lower MFI. By contrast, c-fos shRNA cells exhibited a higher MFI than the control group.ConclusionC-fos increased the expression of P-gp and mdr1 in the HEp-2/VCR cells, and enhanced the efflux function of the cells, thereby contributing to the development of MDR.
Highlights
Laryngeal cancer tends to have a very poor prognosis due to the unsatisfactory efficacy of chemotherapy for this cancer
The a half maximal inhibitory concentration (IC50) of VCR was increased from 0.04 ± 0.01 μmol/l in the normal human epithelial type 2 (HEp-2) cells to 1.7 ± 0.19 μmol/l in the HEp-2/VCR cells (Table 2)
C-fos changes the drug efflux function of P-gp in HEp-2 cells To investigate the role of c-fos in the development of Multidrug resistance (MDR) in HEp-2 cells, we examined the effect of c-fos on the efflux pump activity of P-gp
Summary
Laryngeal cancer tends to have a very poor prognosis due to the unsatisfactory efficacy of chemotherapy for this cancer. The proto-oncogene c-fos has been shown to be involved in the development of MDR in several tumor types, but few studies have evaluated the relationship between c-fos and MDR in laryngeal cancer. We investigated the role of c-fos in MDR development in laryngeal cancer cells (cell line: human epithelial type 2, HEp-2) using the chemotherapeutic vincristine (VCR). Laryngeal cancer is a malignancy that originates in the laryngeal mucosal epithelial tissue. It has become the sixth most common cancer in the world, accounting for 5.7–7.6% of systemic malignant tumors and 7.9–35% of malignant tumors in the otorhinolaryngeal region [1]. The pathogenesis of LSCC may involve smoking, alcohol consumption, air pollution, viral infection, activation of proto-oncogenes and inactivation of tumor suppressor genes [3,4,5,6]. The efficacies of chemotherapy based on vincristine (VCR), methotrexate (MTX), cisplatin (DDP) and 5-fluorouracil (5-FU) are far from ideal
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