Patients with EGFR mutations in non-small cell lung cancer (NSCLC) have been greatly benefited from gefitinib, however, the therapeutic has failed due to the presence of acquired resistance. In this study, we show that gefitinib significantly induces downregulation of Sterol Regulator Element Binding (SREBP1) in therapy-sensitive cells. However, this was not observed in EGFR mutant NSCLC cells with acquired resistance. Lipidomics analysis showed that gefitinib could differently change the proportion of saturated phospholipids and unsaturated phospholipids in gefitinib-sensitive and acquired-resistant cells. Besides, levels of ROS and MDA were increased upon SREBP1 inhibition and even more upon gefitinib treatment. Importantly, inhibition of SREBP1 sensitizes EGFR-mutant therapy-resistant NSCLC to gefitinib both in vitro and in vivo models. These data suggest that sustained de novo lipogenesis through the maintenance of active SRBEP-1 is a key feature of acquired resistance to gefitinib in EGFR mutant lung cancer. Taken together, targeting SREBP1-induced lipogenesis is a promising approach to overcome acquired resistance to gefitinib in EGFR-mutant lung cancer.
Salt stress is one of the most significant adverse abiotic factors, causing crop failure worldwide. So far, a number of salt stress-induced genes, and genes improving salt tolerance have been characterized in a range of plants. Here, we report the isolation and characterization of a salt stress-induced Medicago sativa (alfalfa) gene (MsRCI2A), which showed a high similarity to the yeast plasma membrane protein 3 gene (PMP3) and Arabidopsis RCI2A. The sequence comparisons revealed that five genes of MtRCI2(A-E) showed a high similarity to MsRCI2A in the Medicago truncatula genome. MsRCI2A and MtRCI2(A-E) encode small, highly hydrophobic proteins containing two putative transmembrane domains, predominantly localized in the plasma membrane. The transcript analysis results suggest that MsRCI2A and MtRCI2(A-D) genes are highly induced by salt stress. The expression of MsRCI2A and MtRCI2(A-C) in yeast mutants lacking the PMP3 gene can functionally complement the salt sensitivity phenotype resulting from PMP3 deletion. Overexpression of MsRCI2A in Arabidopsis plants showed improved salt tolerance suggesting the important role of MsRCI2A in salt stress tolerance in alfalfa.
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