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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

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

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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

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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

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2022-08-01 | GSE141630 | GEO

KRAS Mutation Confers Lung Adenocarcinoma Platinum Resistance by Hijacking ALKBH5 Post-translational Modifications–mediated DNA Damage Response

Project description:Constitutively active mutations of KRAS frequently occur in non-small cell lung adenocarcinoma cells (NSCLC). However, the relationship between KRAS constitutive mutations and platinum drug resistance in NSCLC, as well as the underlying mechanism, remains unclear. In this study, we have identified that KRAS constitutive mutations confer resistance to platinum-based drugs in NSCLC. Mechanistically, KRAS mediates platinum resistance in NSCLC cells by enhancing ERK/JNK signaling, which controls post-translational modifications (PTMs) of ALKBH5. This, in turn, leads to an upregulation of m6A methylation in mRNA transcripts related to DNA repair genes. Consequently, the increased m6A methylation of these transcripts results in their mRNA stabilization, thereby protecting NSCLC cells from platinum-induced DNA damage and apoptosis, ultimately conferring platinum drug resistance in NSCLC. Furthermore, our observations indicate that blocking the KRAS mutation-induced increase in m6A methylation of DNA repair-related genes can sensitize NSCLC cells harboring KRAS mutations to platinum exposure. This can be achieved either by overexpressing a SUMOylation-deficient mutant of ALKBH5 or by pharmacologically inhibiting METTL3 enzymatic activity using a small molecule. These interventions significantly enhance the sensitivity of KRAS mutant-bearing NSCLC cells to platinum-based treatments both in vitro and in vivo. In summary, our study uncovers a previously unrecognized mechanism involving KRAS mutations, ALKBH5 PTMs, and increased mRNA m6A levels in DNA repair-related genes, which collectively promote platinum resistance in NSCLC cells.

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Unexpected roles of ATP11B in platinum resistance

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