Original Article
miR-497 may enhance the sensitivity of non-small cell lung cancer cells to gefitinib through targeting the insulin-like growth factor-1 receptor
Abstract
Background: Recently, studies have demonstrated that microRNA-497 (miR-497) plays an important role in modulating tumor cell sensitivity to chemotherapeutic drugs; however, its role in cellular resistance to the effects of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in treatment of non-small cell lung cancer (NSCLC) is not fully understood. In this study, we explored the potential of miR-497 in targeting the insulin-like growth factor-1 receptor (IGF-1R) signaling pathways to overcome gefitinib resistance.
Methods: A gefitinib resistant human lung adenocarcinoma A549 cell line (A549/GR) was established by the method of gefitinib mutagenesis culture. Next, the A549/GR cells were transfected with miR-497 mimics to establish an miR-497 overexpression model, designated A549/GR-miR497-mimic. MTT assay was used to assess cell resistance to gefitinib, and western blot assay was employed to evaluate alterations of IGF-1R and the AKT1 signaling pathway.
Results: We found that A549/GR-miR497-mimic cells (IC50 =33.76±0.97 μmol/L) were more sensitive to gefitinib than the control group (P<0.01). In addition, the expression levels of IGF-1R and phosphorylated AKT1 (p-AKT1) in A549/GR-miR497-mimic cells were reduced.
Conclusions: We demonstrated that miR-497 may have the effect of reversing gefitinib resistance and increasing the sensitivity of NSCLC cells to EGFR-TKIs by inhibiting the expression of IGF-1R and reducing activation of the downstream AKT signaling pathway. Thus, miR-497 plays a vital role in the acquired resistance to EGFR-TKIs, and it may represent a potential therapeutic strategy to treat NSCLC exhibiting resistance to EGFR-TKIs.
Methods: A gefitinib resistant human lung adenocarcinoma A549 cell line (A549/GR) was established by the method of gefitinib mutagenesis culture. Next, the A549/GR cells were transfected with miR-497 mimics to establish an miR-497 overexpression model, designated A549/GR-miR497-mimic. MTT assay was used to assess cell resistance to gefitinib, and western blot assay was employed to evaluate alterations of IGF-1R and the AKT1 signaling pathway.
Results: We found that A549/GR-miR497-mimic cells (IC50 =33.76±0.97 μmol/L) were more sensitive to gefitinib than the control group (P<0.01). In addition, the expression levels of IGF-1R and phosphorylated AKT1 (p-AKT1) in A549/GR-miR497-mimic cells were reduced.
Conclusions: We demonstrated that miR-497 may have the effect of reversing gefitinib resistance and increasing the sensitivity of NSCLC cells to EGFR-TKIs by inhibiting the expression of IGF-1R and reducing activation of the downstream AKT signaling pathway. Thus, miR-497 plays a vital role in the acquired resistance to EGFR-TKIs, and it may represent a potential therapeutic strategy to treat NSCLC exhibiting resistance to EGFR-TKIs.
