Pharmacogenomics of cisplatin sensitivity in non-small cell lung cancer.
Ontology highlight
ABSTRACT:
SUBMITTER: Rose MC
PROVIDER: S-EPMC4411417 | biostudies-literature | 2014 Oct
REPOSITORIES: biostudies-literature
Publications
Pharmacogenomics of cisplatin sensitivity in non-small cell lung cancer.
Rose Maimon C MC Kostyanovskaya Elina E Huang R Stephanie RS
Genomics, proteomics & bioinformatics 20141028 5
Cisplatin, a platinum-based chemotherapeutic drug, has been used for over 30 years in a wide variety of cancers with varying degrees of success. In particular, cisplatin has been used to treat late stage non-small cell lung cancer (NSCLC) as the standard of care. However, therapeutic outcomes vary from patient to patient. Considerable efforts have been invested to identify biomarkers that can be used to predict cisplatin sensitivity in NSCLC. Here we reviewed current evidence for cisplatin sensi ...[more]
Similar Datasets
Project description:BackgroundThe acquisition of drug resistance has been considered as a main obstacle for cancer chemotherapy. Tumor protein 53 target gene 1 (TP53TG1), a p53-induced lncRNA, plays a vital role in the progression of human cancers. However, little is known about the detailed function and molecular mechanism of TP53TG1 in cisplatin resistance of NSCLC.MethodsqRT-PCR analysis was used to detect the expression of TP53TG1, miR-18a and PTEN mRNA in NSCLC tissues and cells. Western blot analysis was performed to determine the protein level of PTEN and cleaved caspase-3. Cell viability and IC50 value were measured by MTT assay. Cell apoptosis was confirmed by flow cytometry assay. Subcellular fractionation assay was used to identify the subcellular location of TP53TG1. Dual-luciferase reporter assay, RNA pull down assay and RNA immunoprecipitation assay were carried out to verify the interaction between TP53TG1 and miR-18a. Xenografts in nude mice were established to verify the effect of TP53TG1 on cisplatin sensitivity of NSCLC cells in vivo.ResultsTP53TG1 level was downregulated in NSCLC tissues and cell lines. Upregulated TP53TG1 enhanced cisplatin sensitivity and apoptosis of A549/DDP cells, while TP53TG1 depletion inhibited cisplatin sensitivity and apoptosis of A549 cells. TP53TG1 suppressed miR-18a expression in A549 cells. Moreover, TP53TG1-mediated enhancement effect on cisplatin sensitivity was abated following the restoration of miR-18a expression in A549/DDP cells, while si-TP53TG1-induced decrease of cisplatin sensitivity and apoptosis was counteracted by miR-18a inhibitor in A549 cells. Furthermore, TP53TG1 promoted PTEN expression via inhibiting miR-18a. Finally, TP53TG1 sensitized NSCLC cells to cisplatin in vivo.ConclusionTP53TG1 increased the sensitivity of NSCLC cells to cisplatin by modulating miR-18a/PTEN axis, elucidating a novel approach to boost the effectiveness of chemotherapy for NSCLC.
| S-EPMC5863826 | biostudies-literature
Project description:Background: Despite great advances in the diagnosis and treatment of non-small cell lung cancer (NSCLC), early diagnosis remains a challenge because patients usually have advanced lung cancer at the time they are diagnosed. The limited efficacy of conventional chemotherapy is another major problem in the treatment of NSCLC. Based on a published set of sequencing data, we find that hsa_circ_0001946 is a circRNA molecule with a significantly different expression level in three cell lines (human normal lung fibroblasts cell line MRC-5, human NSCLC cell line A549, cisplatin-resistant cell line A549/DDP), NSCLC tissues and paired adjacent normal tissues. We believe that hsa_circ_0001946 may have an effect on the progression of NSCLC and its sensitivity to cisplatin. Methods: We focused on investigating the circular RNA, hsa_circ_0001946. RNA interference of hsa_circ_0001946 was carried out in A549 cell lines to determine the effect of reduced hsa_circ_0001946 expression on lung cancer progression and was analyzed by Cell Counting Kit-8 (CCK-8), 5-ethynyl-20-deoxyuridine, clone formation, Hoechst, wound healing, and transwell assays. The nucleotide excision repair (NER) signaling pathway was identified by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Moreover, cellular responses to cisplatin were assessed through CCK-8 and flow cytometry assays. Western blot analysis and host-cell reactivation assay were used to determine the effect of hsa_circ_0001946 on NER signaling. Results: In this study, we found that the reduced expression of hsa_circ_0001946 promoted the viability, proliferation, migration, and invasion of NSCLC cells, as well as inhibition of cell apoptosis. Our findings suggest that hsa_circ_0001946 can affect the sensitivity of NSCLC cells to the chemotherapeutic drug cisplatin via modulation of the NER signaling pathway. Conclusions: Our study demonstrated the role of hsa_circ_0001946 in NSCLC pathogenesis, development, and chemosensitivity, and suggests that hsa_circ_0001946 may serve as a novel biomarker for the diagnosis and prediction of platinum-based chemosensitivity in patients with NSCLC.
| S-EPMC6582772 | biostudies-literature
Project description:BackgroundsAs previously reported, midazolam anesthesia exerts tumor-suppressing effects in non-small cell lung cancer (NSCLC), but the regulating effects of this drug on cisplatin-resistance in NSCLC have not been studied. Thus, we designed this study to investigate this issue and preliminarily delineate the potential molecular mechanisms.MethodsWe performed MTT assay and trypan blue staining assay to measure cell proliferation and viability. Cell apoptosis was examined by FCM. qRT-PCR and immunoblotting were performed to determine the expression levels of genes. The targeting sites between genes were predicted by bioinformatics analysis and were validated by dual-luciferase reporter gene system assay. Mice tumor-bearing models were established and the tumorigenesis was evaluated by measuring tumor weight and volume. Immunohistochemistry (IHC) was used to examine the pro-proliferative Ki67 protein expressions in mice tumor tissues.ResultsThe cisplatin-resistant NSCLC (CR-NSCLC) cells were treated with high-dose cisplatin (50 μg/ml) and low-dose midazolam (10 μg/ml), and the results showed that midazolam suppressed cell proliferation and viability, and promoted cell apoptosis in cisplatin-treated CR-NSCLC cells. In addition, midazolam enhanced cisplatin-sensitivity in CR-NSCLC cell via modulating the miR-194-5p/hook microtubule-tethering protein 3 (HOOK3) axis. Specifically, midazolam upregulated miR-194-5p, but downregulated HOOK3 in the CR-NSCLC cells, and further results validated that miR-194-5p bound to the 3' untranslated region (3'UTR) of HOOK3 mRNA for its inhibition. Also, midazolam downregulated HOOK3 in CR-NSCLC cells by upregulating miR-194-5p. Functional experiments validated that both miR-194-5p downregulation and HOOK3 upregulation abrogated the promoting effects of midazolam on cisplatin-sensitivity in CR-NSCLC cells.ConclusionsTaken together, this study found that midazolam anesthesia reduced cisplatin-resistance in CR-NSCLC cells by regulating the miR-194-5p/HOOK3 axis, implying that midazolam could be used as adjuvant drug for NSCLC treatment in clinical practices.
| S-EPMC8317376 | biostudies-literature
Project description:BackgroundNon-small cell lung cancer (NSCLC) is the major pathological type of lung cancer and accounts for the majority of lung cancer-related deaths worldwide. We investigated the molecular mechanism of prominin 2 (PROM2) involved in cisplatin resistance in NSCLC.Patients and methodsThe GEO database was analyzed to obtain differential genes to target PROM2. Immunohistochemistry and western blotting were used to detect protein expression levels. To examine the role of PROM2 in NSCLC, we overexpressed or knocked down PROM2 by transfection of plasmid or small interfering RNA. In functional experiments, CCK8 was used to detect cell viability. Cell migration and invasion and apoptosis were detected by transwell assay and flow cytometry, respectively. Mechanistically, the regulation of PROM2 by CTCF was detected by ChIP-PCR. In vivo experiments confirmed the role of PROM2 in NSCLC.ResultsGEO data analysis revealed that PROM2 was up-regulated in NSCLC, but its role in NSCLC remains unclear. Our clinical samples confirmed that the expression of PROM2 was markedly increased in NSCLC tissue. Functionally, Overexpression of PROM2 promotes cell proliferation, migration and invasion, and cisplatin resistance. CTCF up-regulates PROM2 expression by binding to its promoter region. In vivo experiments confirmed that PROM2 knockdown could inhibit tumor growth and increase the sensitivity of tumor cells to cisplatin.ConclusionsPROM2 up-regulation in NSCLC can attenuate the sensitivity of NSCLC cells to cisplatin and promote the proliferation, migration and invasion of tumor cells. PROM2 may provide a new target for the treatment of NSCLC.
| S-EPMC10476904 | biostudies-literature
Project description:Drug resistance greatly limits the therapeutic efficacy of treatment of non-small cell lung cancer (NSCLC). One of the important factors is the dysfunction of tumor suppressor p53. Recent studies have suggested that p53 suppresses tumors by regulating number of mitochondrial proteins, including peroxisome proliferator-activated receptor coactivator (PGC1α). Although several studies have confirmed the interaction between p53 and PGC1α, the precise mechanism has not been completely determined in NSCLC. In this study, we investigated the specific signaling between p53 and PGC1α to improve anti-tumor drug effects on NSCLC. We found that low expression of p53 and high expression of PGC1α correlated with shorter survival time of NSCLC patients. In vitro experiments confirmed that NCI-H1299 (p53-null) cells had high levels of PGC1α and were insensitive to cisplatin (CDDP). When PGC1α was knocked down, the sensitivity to cisplatin was increased. Notably, the stability of PGC1α is an important mechanism in its activity regulation. We demonstrated that p53 decreased the stability of PGC1α via the ubiquitin proteasome pathway, which was mediated by protein kinase B (AKT) inhibition and glycogen synthase kinase (GSK-3β) activation. Therefore, p53 may regulate the stability of PGC1α through the AKT/GSK-3β pathway, thus affect the chemosensitivity of NSCLC.
| S-EPMC7471661 | biostudies-literature
Project description:Cytotoxic chemotherapy agents (e.g., cisplatin) are the first-line drugs to treat non-small cell lung cancer (NSCLC) but NSCLC develops resistance to the agent, limiting therapeutic efficacy. Despite many approaches to identifying the underlying mechanism for cisplatin resistance, there remains a lack of effective targets in the population that resist cisplatin treatment. In this study, we sought to investigate the role of cytoplasmic RAP1, a previously identified positive regulator of NF-κB signaling, in the development of cisplatin resistance in NSCLC cells. We found that the expression of cytoplasmic RAP1 was significantly higher in high-grade NSCLC tissues than in low-grade NSCLC; compared with a normal pulmonary epithelial cell line, the A549 NSCLC cells exhibited more cytoplasmic RAP1 expression as well as increased NF-κB activity; cisplatin treatment resulted in a further increase of cytoplasmic RAP1 in A549 cells; overexpression of RAP1 desensitized the A549 cells to cisplatin, and conversely, RAP1 depletion in the NSCLC cells reduced their proliferation and increased their sensitivity to cisplatin, indicating that RAP1 is required for cell growth and has a key mediating role in the development of cisplatin resistance in NSCLC cells. The RAP1-mediated cisplatin resistance was associated with the activation of NF-κB signaling and the upregulation of the antiapoptosis factor BCL-2. Intriguingly, in the small portion of RAP1-depleted cells that survived cisplatin treatment, no induction of NF-κB activity and BCL-2 expression was observed. Furthermore, in established cisplatin-resistant A549 cells, RAP1 depletion caused BCL2 depletion, caspase activation and dramatic lethality to the cells. Hence, our results demonstrate that the cytoplasmic RAP1-NF-κB-BCL2 axis represents a key pathway to cisplatin resistance in NSCLC cells, identifying RAP1 as a marker and a potential therapeutic target for cisplatin resistance of NSCLC.
| S-EPMC5520727 | biostudies-literature
Project description:Small-cell lung cancer is the most aggressive type of lung cancer, characterized by a remarkable response to chemotherapy followed by development of resistance. Here, we describe SCLC subtypes in Mycl- and Nfib-driven GEMM that include CDH1-high peripheral primary tumor lesions and CDH1-negative, aggressive intrapulmonary metastases. Cisplatin treatment preferentially eliminates the latter, thus revealing a striking differential response. Using a combined transcriptomic and proteomic approach, we find a marked reduction in proliferation and metabolic rewiring following cisplatin treatment and present evidence for a distinctive metabolic and structural profile defining intrinsically resistant populations. This offers perspectives for effective combination therapies that might also hold promise for treating human SCLC, given the very similar response of both mouse and human SCLC to cisplatin.
| S-EPMC6581744 | biostudies-literature
Project description:Small cell lung cancer (SCLC) is a fatal tumor type that is prone to drug resistance. In our previous study, we showed that human rhomboid-5 homolog-1 (RHBDF1) was differentially expressed in 5 intrinsic cisplatin-resistant SCLC tissues compared with 5 intrinsic cisplatin-sensitive SCLC tissues by RNA sequencing, which intrigued us. We performed gain- and loss-of-function experiments to investigate RHBDF1 function, bioinformatics analysis, qRT-PCR, western blotting, and immunoprecipitation to elucidate the molecular mechanisms as well as detect RHBDF1 expression in SCLC by immunohistochemistry. We found that RHBDF1 knockdown promoted cell proliferation and cisplatin chemoresistance and inhibited apoptosis in vitro and in vivo. These effects could be reversed by overexpressing RHBDF1 in vitro. Mechanistically, RHBDF1 interacted with YAP1, which increased the phosphorylation of Smad2 and transported Smad2 to the nucleus. Among clinical specimens, the RHBDF1 was a low expression in SCLC and was associated with clinicopathological features and prognosis. We are the first to reveal that RHBDF1 inhibited cell proliferation and promoted cisplatin sensitivity in SCLC and elucidate a novel mechanism through RHBDF1/YAP1/Smad2 signaling pathway which played a crucial role in cisplatin chemosensitivity. Targeting this pathway can be a promising therapeutic strategy for chemotherapy resistance in SCLC.
| S-EPMC11254170 | biostudies-literature
Project description:Cluster of differentiation 44 (CD44) as a transmembrane glycoprotein is found to be expressed in non‑small cell lung cancer (NSCLC), is significantly associated with NSLC progression, metastasis and drug resistance. This study aimed to explore whether CD44 inhibition improves the sensitivity of epidermal growth factor receptor (EGFR) wild‑type NSCLC cells to cisplatin and how it affects wild‑type EGFR in NSCLC cells. Small interfering RNA was used to knockdown CD44 expression in EGFR wild‑type NSCLC cell line H460. Results suggested that CD44 downregulation reduced cell growth, promoted G0/G1 cell cycle arrest and induced cell apoptosis in H460 cells and these effects were evidently enhanced when in combination with cisplatin. Deactivation of EGFR signaling pathway including EGFR phosphorylation and its downstream molecules, targets ERK, AKT1 and SRC which were also observed in CD44‑silenced H460 cells with or without EGF stimulation. Furthermore, the CD44 expression level was positively correlated with wild‑type EGFR level in human lung adenocarcinoma tissues and CD44 inhibition significantly accelerated the degradation of EGFR, indicating that enhanced sensitivity of H460 cells to cisplatin by downregulation of CD44 might be due to EGFR degradation. This study demonstrated that suppression of CD44 deactivated EGFR signals in NSCLC cells with wild‑type EGFR, thereby contributing to the inhibition of cell proliferation and the reinforcement of cisplatin sensitivity. It is suggested that downregulation of CD44 could be a novel potential therapeutic strategy for the treatment of EGFR wild‑type NSCLC.
| S-EPMC7169661 | biostudies-literature
Project description:Chemotherapies based on platinum have been the standard first-line treatment for patients with small-cell lung cancer(SCLC) in the past years. However, the progression of patients occurs mostly due to rapid development of resistance to chemotherapy. In addition, the mechanisms involved in development of cisplatin-resistance in SCLC remain undetermined. Here, we analyzed whole-exome sequencing(WES) datasets from Genomics of Drug Sensitivity in Cancer(GDSC, N=55) and WES data and overall survival(OS) from a published cohort(N=101) to search for cisplatin-resistant target genes and genes associated with poor prognosis. We use our cohort(NCT03162705) as the validation set. We applied single sample gene set enrichment analysis(ssGSEA) to explore the potential molecular mechanisms of cisplatin-resistance. DNAH10 mutations in SCLC was significantly associated with cisplatin-resistance(P=0.0350), poor OS(HR:3.445;P=0.00035) and worse progression-free survival (PFS)(P=0.0142). ssGSEA showed that the negative regulation of FGFR, the SPRY regulation of FGF, and the positive regulation of noncanonical WNT and PI3K/AKT/IKK signaling pathways are differentially up- or downregulated in DNAH10-mutated cell lines. A higher TMB was observed in DNAH10-mutated cell lines. Taken together, DNAH10 mutations may have a potential value in prediction of cisplatin resistance and poor survival in SCLC. Moreover, DNAH10 mutations may have a positive correlation with high TMB in SCLC.
| S-EPMC7053592 | biostudies-literature