SCD1 is required for EGFR-targeting cancer therapy of lung cancer via re-activation of EGFR/PI3K/AKT signals

Abstract

Background 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. Methods CCK-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. Result SCD1 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. Conclusion These findings indicated that inhibition of oncogene SCD1 is required for targeting EGFR therapy in lung cancer.

Lipid Metabolism and Resistance to Anticancer Treatment

“…This is consistent with the crucial role of the receptor tyrosine kinase signaling pathway sustaining upregulation of sterol regulatory element-binding protein (SREBP)-driven de novo lipogenesis (for review [ 40 ]). EGFR-TKI-resistant non-small-cell lung carcinoma (NSCLC) cell lines are characterized by an accumulation of LD and overexpression of Stearoyl-CoA Desaturase 1 (SCD-1), a key enzyme converting saturated fatty acids into unsaturated fatty acids [ 41 ]. Conversely, resistance to mitogen-activated protein kinase (MAPK) pathway inhibitors has generally been associated with increased FAO in BRAF mutated melanoma cells [ 42 ].…”

“…Activation of SCD1 and the subsequent production of mono-unsaturated fatty acids further activates stemness program through Wnt signaling in lung NSCLC [ 69 ] conversely the inhibition of desaturases reduces cancer stemness markers [ 70 ]. HMG-CoA reductase also stimulates stemness via several signaling pathways including the mevalonate, Rho GTPases and YAP/TAZ pathways in brain CSCs [ 33 , 41 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 ]. All of these elements evidence that CSC survival relies on lipid synthesis.…”

Role of Oleic Acid in the Gut-Liver Axis: From Diet to the Regulation of Its Synthesis via Stearoyl-CoA Desaturase 1 (SCD1)

“…Specifically, SCD1 enhances cancer cell mitogenesis and survival, increases tumorigenic capacity and tumor cell invasiveness [110,111]. Even if the antiproliferative effect of SCD1 inhibition is common to many neoplastic cell types including melanoma and lung, bladder, and breast cancer [112,113,114,115], the role of SCD1 in tumorigenesis cannot be generalized. This is demonstrated by the consistently reduced SCD1 activity prostate carcinomas [116].…”

miR-215 Inhibits Colorectal Cancer Cell Migration and Invasion via Targeting Stearoyl-CoA Desaturase

“…For example, decreased SCD expression can inhibit breast cancer progression through the β-catenin signaling pathway [4]. SCD can significantly promote the growth of lung cancer by activating EGFR/PI3K/AKT signaling in tumor tissue [5]. However, the regulatory mechanism of SCD in CRC remains unclear.…”