Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

IGR_CAP1_DOCETAXEL_GE_STUDY_NN

ABSTRACT: Docetaxel is used as a standard treatment in patients with metastatic castration-resistant prostate cancer. However, a large subset of patients develops resistance by mechanisms that remain largely unknown. It is thus important to define the relevant pathways implicated in docetaxel-resistance and validate predictive biomarkers that will allow approaches of personalized treatment. In this aim, we established resistant IGR-CaP1 prostate cancer cell lines to different doses of docetaxel (IGR-CaP1-R cell lines) and investigated gene expression profiles by microarray analyses. We generated a signature of 112 genes potentially implicated in docetaxel-resistance whose expression is highly modified (Fold change M-bM-^IM-% 5). Among these genes, significant modification of expression was observed among cell cycle components in the resistant cells. Hence, we focused on the role of the cell cycle regulator LZTS1 located on chromosome 8p which was under-expressed in all our docetaxel-resistant models. LZTS1 extinction was confirmed at the RNA and protein levels. DNA methylation analysis revealed a stretch of 20 highly methylated CpGs in the region encompassing the exon 1 of LZTS1 promoter in the docetaxel-resistant cells suggesting the existence of an epigenetic regulation of LZTS1 expression in the resistant cells. By using siRNA strategy, we found evidence that LZTS1 plays an important role in the acquisition of the resistant phenotype. In addition, immunohistochemical staining showed that LZTS1 protein was absent or down-regulated in 33% of diagnostic biopsies obtained in patients with metastatic castration-resistant prostate cancer. This heterogeneous labeling suggests that LZTS1 might constitute a predictive biomarker of response to docetaxel chemotherapy. Furthermore, as Cdc25C is a LZTS1 partner in the mitosis regulation, we observed that targeting of Cdc25C with the pharmacological Cdc25C inhibitor NSC 663284 specifically killed the docetaxel-resistant cells. These results strongly suggest that Cdc25C plays a role in docetaxel resistance and that Cdc25C might be a therapeutic target to overcome docetaxel resistance. Altogether our findings identify an important role of LZTS1 in developing docetaxel resistance in prostate cancer through its role in regulating phosphatase Cdc25C. The set of gene expression with 4x44K Agilent ( design 014850) correspond to 6 doses of docetaxel 2?5 to 200 ug/ml) in dual color and dye-swap versus the IGR-Cap1 cell line without docetaxel.

ORGANISM(S): Homo sapiens

SUBMITTER: Philippe DESSEN

PROVIDER: E-MTAB-1221 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Targeting CDC25C, PLK1 and CHEK1 to overcome Docetaxel resistance induced by loss of LZTS1 in prostate cancer.

Al Nakouzi Nader N Cotteret Sophie S Commo Frédéric F Gaudin Catherine C Rajpar Shanna S Dessen Philippe P Vielh Philippe P Fizazi Karim K Chauchereau Anne A

Oncotarget 20140201 3

Docetaxel is used as a standard treatment in patients with metastatic castration-resistant prostate cancer. However, a large subset of patients develops resistance. Understanding resistance mechanisms, which are largely unknown, will allow identification of predictive biomarkers and therapeutic targets. We established resistant IGR-CaP1 prostate cancer cell lines for different doses of Docetaxel. We investigated gene expression profiles by microarray analyses in these cell lines and generated a ...[more]

PMID: 24525428

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Project description:'Prostate cancer is the second cancer diagnosed among men worldwide. Beside approval of new therapies in the last five years, chemotherapeutic agents, docetaxel and cabazitaxel taxanes remain key treatments for metastatic castration resistant prostate cancers. However, primary and acquired resistance to taxanes still emerged in about half of patients. There is therefore an urgent need to discover and understand the taxane resistance mechanisms in order to identify new therapeutic targets. Indeed, targeted therapies that exploit the signaling pathways involved in prostate cancer are required to overcome chemoresistance and improve treatment outcomes. Molecular chaperones play a key role in the regulation of cellular homeostasis and the development of treatment resistance, and are promising therapeutic targets. Using high throughput siRNA functional screening based on a gene expression signature, we identified FKBP7, involved in acquired resistance to docetaxel and cabazitaxel. FKBP7 is a molecular chaperone that has not been studied in human so far. FKBP7 is overexpressed in prostate tumors and its expression is correlated with recurrence in patients who received docetaxel as neoadjuvant therapy. Moreover, FKBP7 is upregulated in taxane resistant prostate cancer cell lines and its expression sustains their growth in vitro and in a mice model of Docetaxel resistance. Using a high throughput proteomic approach, we identified the signaling pathway regulated by FKBP7 which is responsible for the survival of chemoresistant cells. Finally, we proposed a promising therapeutic strategy to overcome both docetaxel and cabazitaxel chemoresistance by targeting the downstream effector of FKBP7. Gene expression was profiled using a 4×44K Human Whole Genome (G4112F, id : 014850) expression array (Agilent Technologies, Santa Clara, Cal.) with a dual color dye-swap competitive hybridization procedure, according to the manufacturer''s instructions. Total RNA from untreated parental IGR-CaP1 cells was used as the RNA reference (NN1). Total RNA from IGR-CaP1 cells resistant to 5nM (NN2), 11.6nM (NN3), 25nM (NN4), 50nM (NN5), 100nM (NN6), and 200nM (NN7) of Docetaxel respectively, were used as samples. Two independent replicates of each samples (a and b) were used. Image analyses (quantification, normalization) were performed with Feature Extraction software (Agilent Technologies) and gene expression analysis was performed using Bioconductor.'

Dataset Information

IGR_CAP1_DOCETAXEL_GE_STUDY_NN

Publications

Targeting CDC25C, PLK1 and CHEK1 to overcome Docetaxel resistance induced by loss of LZTS1 in prostate cancer.

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