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Comparation the mRNA Expression Profile of the MV4-11 Sorafenib Resistant Cells and the Parental Cells

ABSTRACT: Our gene set analysis of MV4-11-R versus MV4-11 indicated decreased depolarization of mitochondria and mitochondrial membrane, mitochondrial dysfunction and anti-apoptosis as other top ranked molecular or cellular functions of differential gene sets. expression of most genes encoding glycolytic enzymes was up-regulated in MV4-11-R cells we revealed a metabolic alteration in sorafenib-resistant cell lines with mitochondrial respiration deficiency, leading to substantial decrease of mitochondria-derived ATP generation and a significant increase in glycolytic activity to maintain sufficient ATP production. Our study revealed a metabolic signature of sorafenib resistance and indicated that increase of glycolytic activity including upregulation of major glycolytic enzymes may be viewed as a marker for early detection of sorafenib resistance in AML patients with FLT3/ITD mutation and glycolytic inhibitors warrant further investigation as alternative therapeutic agents for sorafenib-resistant cells

ORGANISM(S): Homo sapiens

PROVIDER: GSE74666 | GEO | 2016/08/01

SECONDARY ACCESSION(S): PRJNA301124

REPOSITORIES: GEO

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Project description:Objective: identify novel and relevant aspects of Sorafenib action on liver cancer cells. We found that in rat hepatocholangiocarcinoma (LCSC-2) cells, exposure to the MEK/multikinase inhibitor sorafenib did not inhibit ERK phosphorylation nor induced appreciable cell death in the low micromolar range; instead, the drug elicited a raise of intracellular reactive oxygen species (ROS) accompanied by a severe decrease of oxygen consumption and intracellular ATP levels, all changes consistent with mitochondrial damage. Moreover, Sorafenib induced depolarization of isolated rat liver mitochondria, indicating a possible direct effect on the organelle. Microarray analysis of gene expression in sorafenib-trated cells revealed a metabolic reprogramming toward aerobic glycolysis, that likely accounts for resitance to drug toxicity in this cell line. Importantly, cytotoxicity was strongly potentiated by glucose withdrawal from the culture medium or by the glycolytic inhibitor 2-deoxy-glucose, a finding also confirmed in the highly malignant melanoma cell line B16F10. Mechanistic studies revealed that ROS are pivotal to cell killing by the Sorafenib + 2DG combination, and that a low content of intracellular oxidants is associated with resistance to the drug; instead, Thr172phosphorylation/activation of the AMP-activated protein kinase (AMPK), induced by Sorafenib, may exert protective effects, since cytotoxicity was enhanced by an AMPK specific inhibitor and prevented by the AMPK activator Metformin. Overall, this study identifies novel and relevant aspects of Sorafenib action on liver cancer cells, including mitochondrial damage, induction of ROS and a metabolic cell reprogramming towards “glucose addiction”, potentially exploitable in therapy. Microarray analysis of gene expression in sorafenib-trated cells. LCSC-2 cells were incubated with sorafenib 2.5 mM under serum deprivation for 12 hours. The total RNA was isolated from LCSC2, 24h after treatment, using the RNeasy mini kit (Qiagen, Hilden, Germany), RNA was quantified using a UV spectrophotometer and RNA quality and integrity were assessed Agilent 2100 Bioanalyzer (Agilent, Santa Clara, CA, USA). The resulting total RNA was then used to create the biotin-labeled library to be hybridized on GeneChip Rat Gene expression 1.0 st Array (Affymetrix, Santa Clara, CA, USA), according to the recommended experimental protocols provided by the suppliers. The CEL files resulting from the hybridization were analyzed using the Partek® Genomic Suite™ (Partek GS). Gene-level calculation was performed by Robust Multichip Average and normalization by quantile sketch.

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Comparation the mRNA Expression Profile of the MV4-11 Sorafenib Resistant Cells and the Parental Cells

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