原癌基因BRAF通过PGC1α和MITF来调节氧化代谢创新.pptVIP

Journal: cancer Cell Reporter: Xu Wang IF: 23.893 Result 5: several genes involved in oxidative phosphorylation that were dependent on MITF glucose uptake lactate production oxygen consumption Result 6: BRAF Inhibition Leads to Bioenergetic Adaptation by Induction of MITF and PGC1a Result 6: Result 6: PGC-1α level ATP level inhibition of BRAF leads to a bioenergetic crisis that can be variably rescued by induction of the MITF/PGC1a pathway Result 6: Result 6: we found that longitudinal treatment of UACC257 xenografts profoundly inhibited tumor growth, similar to the effects of PLX4032 , whereas A375P cells were insensitive to 2,4-DNP * Oncogenic BRAF Regulates Oxidative Metabolism via PGC1a and MITF Background 50% of melanoma the substitution of valine at position 600 by glutamic acid (BRAF V600E) the BRAF inhibitor vemurafenib (PLX4032) relapse within a few months! MAPK signal passageway activation RAF RAS MEK ERK BRAF抑制剂 细胞增殖和生存 MAPK途径 BRAFV600E P P Purpose Figure out the mechanism of BRAF inhibitor resistance, providing a reliable solution for clinical Background suppression of glycolysis by inhibiting conversion of pyruvate to lactate enhances oxidative phosphorylation and suppressed the growth of breast cancer cell lines Background 3-bromopyruvate suppresses cancer growth Glucose uptake Glycolysis KRas/BRAF(Mut) Survive better colorectal cancers Purpose comprehensively evaluate the effect of BRAF pathway activation on metabolic gene expression and function in melanoma. Materials and Methods 1. Gene set enrichment analysis(GSEA) 2. Western blotting and immunohistochemistry and biopsies 3. Evaluation of gene expression in patient biopsies 4. siRNA delivery and lentivirus infection 5. Cell viability, metabolic assays and flow cytometry 6. Xenograft tumor studies 7. Electron microscopy Result 1: BRAF Regulates Metabolic Reprogramming of Melanomas Result 1: Vemurafenib PD0325901 PD0325901 melanoma cells nonmelanoma cells melanoma cells citric acid cyc