Evaluation of HSP90 inhibitor expsosure on Immune Cell Gene Expression
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA451201 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7050185.fastq.gz | Fastqsanger.gz | |||
| SRR7050186.fastq.gz | Fastqsanger.gz | |||
| SRR7050187.fastq.gz | Fastqsanger.gz | |||
| SRR7050188.fastq.gz | Fastqsanger.gz |
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Project description:Heat shock protein 90 (Hsp90) is an essential evolutionarily conserved molecular chaperone in eukaryotes. Cancer cells rely on Hsp90 to chaperone activated oncoproteins, and its involvement in numerous signaling pathways makes it an attractive target for drug development. Surprisingly, however, the impact of Hsp90 inhibitors on cancer cells is most commonly cytostatic, and efforts to enhance the anti-tumor activity of Hsp90 inhibitors in the clinic remain a significant challenge. In this study, we show that dual inhibition of Wee1 tyrosine kinase and Hsp90 causes prostate cancer cells to undergo apoptosis. Gene-expression profiling revealed that induction of the intrinsic apoptotic pathway by this drug combination coincided with transcriptional down-regulation of Survivin and Wee1, an outcome not seen in cells treated separately with either agent. At the translational level, expression of these two proteins as well as activated Akt was completely abrogated. Similar results were obtained in prostate cancer xenografts. These data establish a novel therapeutic strategy to enhance the efficacy of Hsp90 inhibitors in prostate cancer, and they provide a mechanistic rationale for stimulating the pro-apoptotic activity of Hsp90 inhibitors. In order to explore the mechanism underlying the enhanced cell death caused by Wee1 inhibitorII and 17-AAG combination, we performed microarray analysis using PC3 cells treated with Wee1 inhibitorII alone, 17-AAG alone, or the two drugs in combination. There are 12 samples in total. There are three experimental replicate. Samples 1, 5 and 9 are control (C) (untreated PC3- prostate cancer cells). Samples 2, 6, and 10 are cells treated with Wee1 inhibitor II (W). Samples 3, 7, and 11 are treated with 17-AAG (A), (an Hsp90 inhibitor). Samples 4, 8, and 12 are treated with both Wee1 inhibitorII and 17-AAG (WA). Samples 5 was removed from our analysis due to weak signal.
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Project description:Purpose: The growth and survival of NF2-deficient cells are enhanced by the activation of multiple signaling pathways including ErbB2/IGF-1R/Met, PI3K/Akt, and Ras/Raf/Mek/Erk1/2. The ubiquitously expressed chaperone protein HSP90 is known to be essential for the stabilization of these signaling molecules. We aim to evaluate the effect of the HSP90 inhibition on the signaling pathways activated in NF2-related tumors. We tested the efficacy of the newly synthesized small molecule NXD30001 which was shown to be more potent in HSP90 inhibition in vitro and less toxic in vivo than already existing HSP90 inhibitors. Experimental Design: The anti-proliferative activity of NXD30001 was tested in NF2-deficient mouse cells in vitro, and its anti-tumor efficacy was verified in an NF2-deficient allograft model in vivo. The underlying molecular alteration in vitro and in vivo was further characterized by a global transcriptome approach. Results: NXD30001 was found to induce degradation of client proteins and to suppress proliferation in NF2-deficient cells in vitro and in vivo. Differential expression analysis further identified subsets of genes implicated in cell proliferation, survival, vascularization, and Schwann cell differentiation, whose expression were altered by NXD30001 treatment. Conclusions: NXD30001 is a potent HSP90 inhibitor showing significant antitumor activity against NF2-related tumor cells in vitro and in vivo, and represents a promising option for novel NF2 therapies. Global RNA expression in NXD30001-treated and untreated matched NF2-deficiemt cultured cells (in vitro) and allograft tumors (in vivo) were compared by RNA-Seq.
2013-06-06 | E-GEOD-40187 | biostudies-arrayexpress
Project description:Purpose: The growth and survival of NF2-deficient cells are enhanced by the activation of multiple signaling pathways including ErbB2/IGF-1R/Met, PI3K/Akt, and Ras/Raf/Mek/Erk1/2. The ubiquitously expressed chaperone protein HSP90 is known to be essential for the stabilization of these signaling molecules. We aim to evaluate the effect of the HSP90 inhibition on the signaling pathways activated in NF2-related tumors. We tested the efficacy of the newly synthesized small molecule NXD30001 which was shown to be more potent in HSP90 inhibition in vitro and less toxic in vivo than already existing HSP90 inhibitors. Experimental Design: The anti-proliferative activity of NXD30001 was tested in NF2-deficient mouse cells in vitro, and its anti-tumor efficacy was verified in an NF2-deficient allograft model in vivo. The underlying molecular alteration in vitro and in vivo was further characterized by a global transcriptome approach. Results: NXD30001 was found to induce degradation of client proteins and to suppress proliferation in NF2-deficient cells in vitro and in vivo. Differential expression analysis further identified subsets of genes implicated in cell proliferation, survival, vascularization, and Schwann cell differentiation, whose expression were altered by NXD30001 treatment. Conclusions: NXD30001 is a potent HSP90 inhibitor showing significant antitumor activity against NF2-related tumor cells in vitro and in vivo, and represents a promising option for novel NF2 therapies.
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