Targeting metabolic vulnerability in mitochondria conquers MEK inhibitor resistance in KRAS-mutant lung cancer

MEK is a canonical effector of mutant KRAS; however, MEK inhibitors fail to yield satisfactory clinical outcomes in KRAS-mutant cancers. Here, we identified mitochondrial oxidative phosphorylation (OXPHOS) induction as a profound metabolic alteration to confer KRAS-mutant non-small cell lung cancer (NSCLC) resistance to the clinical MEK inhibitor trametinib. Metabolic flux analysis demonstrated that pyruvate metabolism and fatty acid oxidation were markedly enhanced and coordinately powered the OXPHOS system in resistant cells after trametinib treatment, satisfying their energy demand and protecting them from apoptosis. As molecular events in this process, the pyruvate dehydrogenase complex (PDHc) and carnitine palmitoyl transferase IA (CPTIA), two rate-limiting enzymes that control the metabolic flux of pyruvate and palmitic acid to mitochondrial respiration were activated through phosphorylation and transcriptional regulation. Importantly, the co-administration of trametinib and IACS-010759, a clinical mitochondrial complex I inhibitor that blocks OXPHOS, significantly impeded tumor growth and prolonged mouse survival. Overall, our findings reveal that MEK inhibitor therapy creates a metabolic vulnerability in the mitochondria and further develop an effective combinatorial strategy to circumvent MEK inhibitors resistance in KRAS-driven NSCLC.

Transplantation of human amnion epithelial cells improves learning and memory function in Alzheimer’ s disease-like pathology rat model / 中国病理生理杂志

[ ABSTRACT] AIM:To observe the treatment effect and its immune regulation of human amnion epithelial cells ( hAECs) on Alzheimer’ s disease ( AD)-like pathology rat model.METHODS: The hAECs were isolated from amnion with trypsin digestion, and the phenotype of hAECs was analyzed by flow cytometry.SD rats ( n=48) were randomly divid-ed into sham control group, model group, medium group and hAECs group.AD-like pathology rat model was induced by bilateral intraventricular injection of lipopolysaccharide (LPS).hAECs (5 ×105) were injected into the hippocampus of the AD-like pathology rats.At 2 weeks after transplantation, the animals were tested by Morris water maze to observe the function of learning and memory.The pathological change of the brain was observed by HE staining.The expression of am-yloid β-protein 42 (Aβ42) and Tau protein and the level of acetylcholine (ACh) in the injury brain were determined by immunohistochemistry.The survival and differentiation of hAECs in the hippocampus were measured by immunofluorescent technique.The percentages of lymphocyte subsets in the peripheral blood mononuclear cells were analyzed by flow cytome-try.The contents of serum cytokines were detected by cytometric bead array.RESULTS:Compared with model group and medium group, hAECs group showed shortened escape latency ( P<0.01) , increased frequency of going through the plat-form (P<0.05), reduced loss of hippocampal neurons, decreased expression of Tau protein and Aβ42 in the hippocampus (P<0.05), increased ACh level in the hippocampus (P<0.05), decreased percentages of Th1 and Th17 subsets, in-creased percentages of Th2 and Treg cells ( P<0.05) , decreased concentrations of IFN-γand IL-2 in the serum, and in-creased concentration of IL-4 ( P<0.05 ) .CONCLUSION: hAECs improve the cognitive learning and memory function and alleviate pathologic damage of hippocampus through immune regulation in AD-like pathology rats.