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Gene expression data from human NSCLC U1810 residual clones 9 days after a one-hour pulse treatment with cisplatin

ABSTRACT: Background: The platinum compounds cisplatin and carboplatin are the mainstay of chemotherapy for lung cancer; however, treatment failure remains a critical issue since about 60% of all non-small cell lung cancer (NSCLC) patients display intrinsic platinum resistance. Methods: We analyzed global gene expression profiles in NSCLC clones surviving a pulse treatment with cisplatin by microarray and mapped deregulated signaling networks in silico by Ingenuity Pathway Analysis (IPA). Results: Cisplatin-surviving NSCLC clones were demonstrated to have heterogeneous gene expression patterns both in terms of the number and the identity of the altered genes. Genes involved in Wnt signaling pathway (DKK1), DNA repair machinery (XRCC2) and cell-cell/ cell-matrix interaction (FMN1 and LGALS9) were among the top deregulated genes by microarray and were subsequently validated by q-RT-PCR. We focused on DKK1, which was previously reported to be overexpressed in NSCLC. IPA network analysis revealed coordinate up-regulation of several DKK1 transcriptional regulators (TCF4, EZH2, DNAJB6 and HDAC2) in cisplatin-surviving clones. Knockdown of DKK1 by siRNA sensitized untreated NSCLC cells to cisplatin, illustrating a putative role of DKK1 in intrinsic platinum resistance. Conclusions: Gene expression analysis identified DKK1 as a putative cisplatin resistance marker and a potential novel therapeutic target to overcome platinum resistance in NSCLC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE48244 | GEO | 2014/04/04

SECONDARY ACCESSION(S): PRJNA209344

REPOSITORIES: GEO

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Gene expression data from human NSCLC U1810 residual clones 9 days after a one-hour pulse treatment with cisplatin

Project description:Background: The platinum compounds cisplatin and carboplatin are the mainstay of chemotherapy for lung cancer; however, treatment failure remains a critical issue since about 60% of all non-small cell lung cancer (NSCLC) patients display intrinsic platinum resistance. Methods: We analyzed global gene expression profiles in NSCLC clones surviving a pulse treatment with cisplatin by microarray and mapped deregulated signaling networks in silico by Ingenuity Pathway Analysis (IPA). Results: Cisplatin-surviving NSCLC clones were demonstrated to have heterogeneous gene expression patterns both in terms of the number and the identity of the altered genes. Genes involved in Wnt signaling pathway (DKK1), DNA repair machinery (XRCC2) and cell-cell/ cell-matrix interaction (FMN1 and LGALS9) were among the top deregulated genes by microarray and were subsequently validated by q-RT-PCR. We focused on DKK1, which was previously reported to be overexpressed in NSCLC. IPA network analysis revealed coordinate up-regulation of several DKK1 transcriptional regulators (TCF4, EZH2, DNAJB6 and HDAC2) in cisplatin-surviving clones. Knockdown of DKK1 by siRNA sensitized untreated NSCLC cells to cisplatin, illustrating a putative role of DKK1 in intrinsic platinum resistance. Conclusions: Gene expression analysis identified DKK1 as a putative cisplatin resistance marker and a potential novel therapeutic target to overcome platinum resistance in NSCLC. U1810 cells were sparsely seeded for clonogenic survival assay in three separate experiments (replicate 1-3), left untreated or treated with cisplatin for 1 h and then kept for 9 days to assay long-term effects of a single pulse treatment.

2014-04-04 | E-GEOD-48244 | biostudies-arrayexpress

Identification of proteins deregulated by platinum-based chemotherapy as novel biomarkers and therapeutic targets in non-small cell lung cancer

Project description:Platinum-based chemotherapy remains the cornerstone of treatment for most people with non-small cell lung cancer (NSCLC), either as adjuvant therapy in combination with a second cytotoxic agent or in combination with immunotherapy. Resistance to therapy, either in the form of primary refractory disease or evolutionary resistance, remains a significant issue in the treatment of NSCLC. Hence, predictive biomarkers and novel combinational strategies are required to improve the effectiveness and durability of treatment response for people with NSCLC. The aim of this study was to identify novel biomarkers and/or druggable proteins from deregulated protein networks within non-oncogene driven disease that are involved in the cellular response to cisplatin. Following exposure of NSCLC cells to cisplatin, in vitro quantitative mass spectrometry was applied to identify altered protein response networks. A total of 65 proteins were significantly deregulated following cisplatin exposure. These proteins were assessed to determine if they are druggable targets using novel machine learning approaches and to identify whether these proteins might serve as prognosticators of platinum therapy. Our data demonstrate novel candidates and drug-like molecules warranting further investigation to improve response to platinum agents in NSCLC.

2021-06-15 | PXD024209 | panorama

CRTAC1 Enhances the Chemosensitivity of Non-Small Cell Lung Cancer to Cisplatin by Eliciting RyR-mediated Calcium Release and Inhibiting Akt1 Expression

Project description:Sensitivity to platinum-based combination chemotherapy is associated with a favorable prognosis in the patients of non-small cell lung cancer (NSCLC). Here, our results obtained from analyses of the Gene Expression Omnibus database of NSCLC patients showed that cartilage acidic protein 1 (CRTAC1) plays a role in the response to platinum-based chemotherapy. Overexpression of CRTAC1 increased sensitivity to cisplatin in vitro, whereas knockdown of CRTAC1 decreased chemosensitivity of NSCLC cells. In vivo mouse experiments showed that CRTAC1 overexpression increased the antitumor effects of cisplatin. CRTAC1 overexpression promoted NFAT transcriptional activation by increasing intracellular Ca2+ levels, thereby inducing its regulated STUB1 mRNA transcription and protein expression, accelerating Akt1 protein degradation, and in turn enhancing cisplatin-induced apoptosis. Taken together, the present results indicate that CRTAC1 overexpression increases the chemosensitivity of NSCLC to cisplatin treatment by inducing Ca2+-dependent Akt1 degradation and apoptosis, suggesting the potential of CRTAC1 as a biomarker for predicting cisplatin chemosensitivity. Our results further reveal that modulating the expression of CRTAC1 could be a new strategy for increasing the efficacy of cisplatin in chemotherapy of NSCLC patients.

2023-08-29 | PXD041782 | Pride

Proteome Analysis of Non-Small Cell Lung Cancer Cell Line Secretomes and Patient Sputum Reveals Biofluid Biomarker Candidates for Cisplatin Response Prediction

Project description:We profiled the secretomes of six NSCLC cell lines with varying IC50-values for cisplatin, using label-free GeLC-MS/MS-based proteomics. Out of a total dataset of 2618 proteins, 304 proteins showed significant differences in expression levels between cisplatin sensitive and insensitive cell lines. Functional data mining revealed that the secretion of typically extracellular factors was associated with a higher sensitivity towards cisplatin, while cisplatin insensitivity correlated with increased secretion of theoretically intra-cellular proteins, in line with enhanced levels of non-conventional secretion in cisplatin insensitive cell lines. Stringent statistical analysis and quantitative filtering yielded 41 top biomarker candidates, many of which could also be detected in NSCLC patient sputum using label-free GeLC-MS/MS-based proteomics. A published gene expression dataset was used to determine which of our top secretome cisplatin response prediction candidates might have predictive value in terms of overall survival in patients that received platinum-based treatment. This analysis yielded two cisplatin sensitivity (UGGT1 and MATN2) and one cisplatin resistance (MAP4) candidates that may serve as potential biomarkers for cisplatin response prediction in NSCLC patients in the future.

2022-02-28 | PXD005830 | Pride

Unexpected roles of ATP11B in platinum resistance

Project description:Platinum compounds display clinical activity against a wide variety of solid tumors. However, resistance to these agents is a major limitation in cancer therapy. Reduced platinum uptake and increased platinum export are examples of resistance mechanisms that limit the extent of DNA damage. Here, we report the discovery and characterization of the role of ATP11B, a P-type ATPase membrane protein, in cisplatin resistance. ATP11B gene silencing restored the sensitivity of ovarian cancer cell lines to cisplatin in vitro. Combined therapy of cisplatin and ATP11B-siRNA significantly decreased cancer growth in mice bearing ovarian tumors derived from cisplatin-sensitive and -resistant cells. In vitro mechanistic studies on cellular platinum content and cisplatin efflux-kinetics indicated that ATP11B enhances the export of cisplatin from cells. The co-localization of ATP11B with fluorescent cisplatin and with vesicular trafficking proteins such as syntaxin-6 (STX6) and vesicular associated membrane protein 4 (VAMP4) strongly suggests that ATP11B contributes to secretory vesicular transport of cisplatin from Golgi to plasma membrane. In conclusion, silencing ATP11B expression might be a therapeutic strategy to overcome cisplatin resistance. We performed the transfection of control-siRNA and ATP11B-siRNA to both cisplatin-sensitive A2780-PAR and cisplatin-resistant A2780-CP20 cells respectively.

2013-01-23 | E-GEOD-43694 | biostudies-arrayexpress

Platinum chemotherapy induces diverse evolutionary trajectories in high grade serous ovarian cancer

Project description:Cisplatin- and carboplatin-resistant high-grade serous ovarian cancer (HGSC) cells were generated and new lines were created from single cell clones. All cells were derived from a common ancestral line, Ovcar4. RNA sequencing was performed to examine transcriptional changes related to acquisition of platinum resistance.

2022-08-01 | GSE141630 | GEO

Global profiling of platinum drugs resistant genes in A549 cell lines

Project description:Non Small Cell Lung Cancer (NSCLC) causes the premature death of over 1 million people worldwide each year, but remains inadequately understood at the molecular level. To provide new insights for NSCLC treatment we performed a molecular characterisation of wild type and platinum drugs resistance in A549 cells. Transcriptome profiling revealed contrasting patterns of gene expression in sensitive and resistant cells and identified genes whose expression was highly correlated with the platinum drugs. Our results revealed a gene set of 15 transcripts whose expression was highly correlated with platinum-resistance in NSCLC A549 cell lines.

2012-02-24 | E-MEXP-3123 | biostudies-arrayexpress

Unexpected roles of ATP11B in platinum resistance

2013-01-23 | GSE43694 | GEO

MicroRNA profiling of cisplatin-resistant and cisplatin-sensitive ovarian cancer cells

Project description:Platinum resistance is a major drawback in the treatment of ovarian cancer. Evidence suggests that microRNAs are key players in the initiation, progression, and drug resistance of cancer cells. However, the precise miRNAs dysregulated and contributing to platinum resistance in ovarian cancer cells have not been fully elucidated. Here, we conducted a miRNA expression profiling of cisplatin-sensitive (A2780) and cisplatin-resistant (CP20 and CIS) ovarian cancer cells to identify potential miRNAs involved in platinum resistance.

2020-11-20 | GSE161784 | GEO

Gene expression data from parental HeLa and Dickkopf-1 (Dkk1) knockout HeLa cells after Cisplatin treatment

Project description:Infection with oncogenic human papillomavirus (HPV) is a major cause for the development of cervical cancer, which is mainly driven by the expression of the HPV E6 and E7 oncoproteins. We uncovered that the concentration levels of the putative tumor suppressor Dickkopf-1 (Dkk1) are restricted in cervical cancer cells by HPV E6 expression due to the E6-mediated proteolytic degradation of p53, which is a transcriptional regulator of Dkk1. Moreover, we found that Dkk1 is critically involved in the pro-apoptotic Cisplatin response of these cells, as Dkk1 repression was associated with an increased resistance towards the chemotherapeutic compound. This could be of high relevance for cervical cancer treatments, which usually involve Cisplatin for standard care. Although Dkk1 is a major antagonist of the canonical Wnt signaling, the differential response towards Cisplatin observed in Dkk1-depleted cells was not associated to an activation of this pathway. To elucidate alternative underlying mechanisms, we performed Affymetrix Gene Expression analyses comparing the transcriptome of Cisplatin-treated parental HeLa to CRISPR/Cas9-generated Dkk1 knockout (KO) HeLa cells. These revealed that Dkk1 depletion is linked to an impairment of the pro-apoptotic JNK/AP-1 pathway in cervical cancer cells, suggesting that Dkk1 drives Cisplatin-mediated apoptosis via activation of this signaling hub.

2022-08-16 | GSE200748 | GEO

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