| ObjectiveTo investigate the molecular mechanisms of multidrug resistance induced bycytoplasmic M-CSF in MCF-7breast cancer cells.MethodsMCF-7cells stable expressing cytoplasmic M-CSF were constructed in thelaboratory. The expression of M-CSF, Mdr-1and PI3K/Akt/GSK3β/β-cateninsignaling molecules was detected by Western blotting. The cells survival wasobserved by MTT assays. The role of Mdr-1was detected adriamycinauto-fluorescence. The subcellular localization of β-catenin was detected byimmunofluorescence and Western blotting.Results1.Cytoplasmic M-CSF up-regulated the expression of Mdr-1(p<0.05) andenhances its resistance to5-FU and Paclitaxel(p<0.05) in MCF-7cells. CytoplasmicM-CSFchallenged the subcellular localization of adriamycin in MCF-7cells anddecreased the adriamycin accumulation in the nucleusof MCF-7cells.2.Cytoplasmic M-CSF up-regulated the expression of total β-catenin and nuclearβ-catenin(p<0.05) and promoted β-catenin translocation from cytoplasm to nucleusinMCF-7cells.3.cytoplasmic M-CSF induced the expression of p-PI3K, p-Akt1, p-GSK3β andMdr-1(p<0.05) and activated PI3K/Akt/GSK3β/β-catenin signaling. Inhibiting ofPI3K/Akt/GSK3β/β-catenin signaling by LY294002, or SH-6, and or FH535repressed Mdr-1expression (p<0.05). LY294002, SH-6and FH535reversed the up-regulationof Mdr-1induced by cytoplasmic M-CSF in various degrees (p<0.05), enhanced thesensitivity of MCF-7-M cells to5-FU (p<0.01) and TAX (p<0.01). and inhibitedadriamycin excretionfrom nucleus to cytoplasm of MCF-7cells. Thereby reversedmulti-drug resistance of MCF-7cellsmediated by cytoplasmic M-CSF.ConclusionsCytoplasmic M-CSF induces multi-drug resistance by up-regulating Mdr-1expression mediated through PI3K/Akt/GSK3β/β-catenin signaling in MCF-7breastcancer cells. |
