Unknown,Transcriptomics,Genomics,Proteomics

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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 Sorafenib resistant cells MV411-R VS. parental MV4-11 cells. Biological replicates: 3 control replicates, 3 treated replicates.

ORGANISM(S): Homo sapiens

SUBMITTER: Amin Huang

PROVIDER: E-GEOD-74666 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:OBJECTIVE: Sorafenib is effective in hepatocellular carcinoma (HCC), but patients ultimately present disease progression. Molecular mechanisms underlying acquired resistance are still unknown. Herein, we characterize the role of tumor-initiating cells (T-ICs) and signaling pathways involved in sorafenib resistance. DESIGN: HCC xenograft mice treated with sorafenib (n=22) were explored for responsiveness (n=5) and acquired resistance (n=17). Mechanism of acquired resistance were assessed by: 1) Role of T-ICs by in vitro sphere formation and in vivo tumorigenesis assays using NOD/SCID mice, 2) Activation of alternative signaling pathways and 3) Efficacy of anti-FGF and anti-IGF drugs in experimental models. Gene expression (microarray, qRT-PCR) and protein analyses (immunohistochemistry, western blot) were conducted. A novel gene signature of sorafenib resistance was generated and tested in 2 independent cohorts. RESULTS: Sorafenib-acquired resistance tumors showed significant enrichment of T-ICs (164 cells needed to create a tumor) vs. sorafenib-sensitive tumors (13400 cells) and non-treated tumors (1292 cells), p<0.001. Tumors with sorafenib-acquired resistance were enriched with IGF and FGF signaling cascades (FDR<0.05). In vitro, cells derived from sorafenib-acquired resistant tumors and two sorafenib-resistant HCC cell lines were responsive to IGF or FGF inhibition. In vivo, FGF blockade delayed tumor growth and improved survival in sorafenib-resistant tumors. A sorafenib-resistance 175-gene signature was characterized by enrichment of progenitor-cell features, aggressive tumoral traits and predicted poor survival in 2 cohorts (n=442 HCC patients). CONCLUSION: Acquired resistance to sorafenib is driven by tumor initiating cells with enrichment of progenitor markers and activation of IGF and FGF signaling. Inhibition of these pathways would benefit a subset of patients after sorafenib progression. Transcriptomic profile of subcutaneous Huh7 cells-derived tumors treated with sorafenib that developed acquired resistance to the drug (n=4), remain responsive to sorafenib (n=3) or were treated with brivanib after development of resistance (n=3). Gene profiling of hepatospheres generated from tumors with acquired resistance to sorafenib (n=3) and non-treated tumors (n=3) was also analyzed.

Project description:Relapsed/refractory Hodgkin lymphoma (HL) is an unmet medical need requiring new therapeutic options. Interactions between the histone deacetylase inhibitor Givinostat and the RAF/MEK/ERK inhibitor Sorafenib were examined in HDLM-2 and L-540 HL cell lines. Exposure to Givinostat/Sorafenib induced a synergistic inhibition of cell growth (range, 70- 80%) and a dramatic increase in cell death (up to 96%) due to increased H3 and H4 acetylation and strong mitochondrial injury. Gene expression profiling indicated that the synergistic effects of Givinostat/Sorafenib treatment are associated with the modulation of cell cycle and cell death pathways. Exposure to Givinostat/Sorafenib resulted in sustained production of reactive oxygen species (ROS) and activation of necroptotic cell death. The necroptosis inhibitor Necrostatin-1 prevented Givinostat/Sorafenib-induced ROS production, mitochondrial injury, activation of BH3-only protein BIM and cell death. Knockdown experiments identified BIM as a key signaling molecule that mediates Givinostat/Sorafenib-induced oxidative death of HL cells. Furthermore, in vivo xenograft studies demonstrated a 50% reduction in tumor burden (P < 0.0001), a 5- to 15-fold increase in BIM expression (P M-bM-^IM-$.0001) and a 4-fold increase in tumor necrosis in Givinostat/Sorafenib-treated animals compared to mice that received the single agents. These results provide a rationale for exploring Givinostat/Sorafenib combination in relapsed/refractory HL. The Hodgkin lymphoma cell line L-540 was obtained from the DSMZ (Braunschweig, Germany, EU). Cells were routinely maintained in RPMI medium 1640 (Lonza, Basel, Switzerland) supplemented with 20% FBS (Lonza) and 2 mM glutamine (Lonza). Cells were maintained at 37M-BM-0C in a water-saturated atmosphere of 5% CO2 in air. 10x10^6 L-540 cells were seeded in 75 cm2 flask and, after 24 hrs, cells were treated with 100 nM Givinostat (Italfarmaco SpA, Milan, Italy, EU) and/or 5 M-BM-5M sorafenib (Bayer, Berlin,M-bM-^@M-(Germany, EU) in culture medium for 24 hours. At the end of treatment, cells were collected and RNA was extracted.

Project description:Relapsed/refractory Hodgkin lymphoma (HL) is an unmet medical need requiring new therapeutic options. Interactions between the histone deacetylase inhibitor Givinostat and the RAF/MEK/ERK inhibitor Sorafenib were examined in HDLM-2 and L-540 HL cell lines. Exposure to Givinostat/Sorafenib induced a synergistic inhibition of cell growth (range, 70- 80%) and a dramatic increase in cell death (up to 96%) due to increased H3 and H4 acetylation and strong mitochondrial injury. Gene expression profiling indicated that the synergistic effects of Givinostat/Sorafenib treatment are associated with the modulation of cell cycle and cell death pathways. Exposure to Givinostat/Sorafenib resulted in sustained production of reactive oxygen species (ROS) and activation of necroptotic cell death. The necroptosis inhibitor Necrostatin-1 prevented Givinostat/Sorafenib-induced ROS production, mitochondrial injury, activation of BH3-only protein BIM and cell death. Knockdown experiments identified BIM as a key signaling molecule that mediates Givinostat/Sorafenib-induced oxidative death of HL cells. Furthermore, in vivo xenograft studies demonstrated a 50% reduction in tumor burden (P < 0.0001), a 5- to 15-fold increase in BIM expression (P M-bM-^IM-$.0001) and a 4-fold increase in tumor necrosis in Givinostat/Sorafenib-treated animals compared to mice that received the single agents. These results provide a rationale for exploring Givinostat/Sorafenib combination in relapsed/refractory HL. The Hodgkin lymphoma cell line HDLM-2 was obtained from the DSMZ (Braunschweig, Germany, EU). Cells were routinely maintained in RPMI medium 1640 (Lonza, Basel, Switzerland) supplemented with 20% FBS (Lonza) and 2 mM glutamine (Lonza). Cells were maintained at 37M-BM-0C in a water-saturated atmosphere of 5% CO2 in air. 10x10^6 HDLM-2 cells were seeded in 75 cm2 flask and, after 24 hrs, cells were treated with 100 nM Givinostat (Italfarmaco SpA, Milan, Italy, EU) and/or 5 M-BM-5M sorafenib (Bayer, Berlin,M-bM-^@M-(Germany, EU) in culture medium for 24 hours. At the end of treatment, cells were collected and RNA was extracted.

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

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