Abstract
BackgroundCancer cells are characterized by aberrant activation of lipid biosynthesis, producing saturated fatty acids and monounsaturated fatty acids via stearoyl-CoA desaturases (SCD) for regulating metabolic and signaling platforms. SCD1 overexpression functions as an oncogene in lung cancer and predicts a poor clinical outcome. This study aimed to investigate the role of SCD1 inhibition by EGFR inhibitor (Gefitinib)-based anti-tumor therapy of lung cancer both in vitro and in vivo.MethodsCCK-8 assay was performed to determine cell viability. The SCD1 mRNA level was detected by qPCR. The protein levels were assessed by Western blotting. E-cadherin and N-cadherin levels were determined by immunofluorescence. Apoptosis detection was conducted by flow cytometry. Cell migration or invasion was evaluated by transwell assay. The tumor sizes and tumor volumes were calculated in nude mice by subcutaneous injection of A549 cells transfected with vector of pcDNA3.1-SCD1 or negative control. Expression of Ki-67 was detected by immunohistochemistry.ResultSCD1 up-regulated expression was observed in lung cancer cell lines. Cells with overexpressed SCD1 had high IC50 values for Gefitinib in A549 and H1573 cell lines. Overexpression of SCD1 inhibited Gefitinib-induced apoptosis, decreased cell vitality and impaired ability of migration and invasion, while these effects were counteracted by A939572. Mechanistically, SCD1 promoted the activation of proliferation and metastasis-related EGFR/PI3K/AKT signaling, and up-regulated epithelial to mesenchymal transition (EMT) phenotype in the two cell lines, which was restored by SCD1 inhibition. Furthermore, in spite of EGFR inhibition, overexpression of SCD1 in vivo significantly promoted tumor growth by activating EGFR/PI3K/AKT signaling in tumor tissues, but A939572 treatment restricted SCD1-induced tumor progression and inhibited EMT phenotype of cancer cells in vivo.ConclusionThese findings indicated that inhibition of oncogene SCD1 is required for targeting EGFR therapy in lung cancer.
Highlights
Cancer cells are characterized by aberrant activation of lipid biosynthesis, producing saturated fatty acids and monounsaturated fatty acids via stearoyl-CoA desaturases (SCD) for regulating metabolic and signaling platforms
Overexpressed SCD1 promotes the resistance of epidermal growth factor receptor (EGFR) inhibitor‐based therapy The up-regulation of SCD1 in lung cancer cell lines A549, H838 and H1573 should be confirmed
The results indicated that the mRNA and protein levels of SCD1 were remarkably increased in cancer cell lines when compared to human bronchial epithelial cells BEAS-2B (Fig. 1a, b)
Summary
Cancer cells are characterized by aberrant activation of lipid biosynthesis, producing saturated fatty acids and monounsaturated fatty acids via stearoyl-CoA desaturases (SCD) for regulating metabolic and signaling platforms. SCD1 overexpression functions as an oncogene in lung cancer and predicts a poor clinical outcome. This study aimed to investigate the role of SCD1 inhibition by EGFR inhibitor (Gefitinib)-based anti-tumor therapy of lung cancer both in vitro and in vivo. NSCLC accounted for more than 85% of all lung cancers [2]. Due to large proportion of NSCLC patients, the locally advanced or metastatic stage has already been developed at the time of diagnosis, and the prognosis for advanced-stage disease is extremely unsatisfactory with an overall 5-year survival rate being 17%. Apart from the current surgery, radiotherapy and platinum-based chemotherapy, the inhibitors of EGFR by targeting tyrosine kinase inhibitors (TKIs) such as gefitinib or eloritinib contributed to clinical successes, but the patients would eventually acquire drug resistance [3,4,5]
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