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Oxaliplatin resistance is enhanced by saracatinib via upregulation of ABCG1 and Wnt/β-catenin signaling in hepatocellular carcinoma

ABSTRACT: Oxaliplatin resistance is enhanced by saracatinib via upregulation of ABCG1 and Wnt/β-catenin signaling in hepatocellular carcinoma

PROVIDER: PRJNA529896 | ENA |

REPOSITORIES: ENA

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Oxaliplatin resistance is enhanced by saracatinib via upregulation of ABCG1 and Wnt/β-catenin signaling in hepatocellular carcinoma

Project description:Background:Oxaliplatin-resistant hepatocellular carcinoma (HCC) is associated with increased insulin-like growth factor 1 (IGF1) paracrine signaling, and the IGF1 receptor can be downregulated by inhibition of Src kinases. Therefore, we sought to determine whether Src inhibition and oxaliplatin treatment exerted synergistic effects on HCC cell lines. Methods: The antitumor effects of combined treatment with saracatinib and oxaliplatin on proliferation were evaluated in HCC cells as well as in saracatinib- and oxaliplatin-resistant HCC cell lines using cell viability assays, plate colony formation assays, and cell cycle distribution detection. RNA sequencing was used to explore the resistance mechanism, and the effects on ABCG1 and Wnt signaling in oxaliplatin resistance were confirmed. Results: Chemotherapy with oxaliplatin and saracatinib individually induced strong anti-HCC effects, while combined or sequential treatment of HCC cells with these two drugs exhibited reduced efficacy compared to treatment with the single drugs. Furthermore, treatment with saracatinib caused oxaliplatin resistance. RNA sequencing revealed 458 genes that were altered by treatment with saracatinib and oxaliplatin. Of these, the gene encoding the ATP-binding cassette transporter G1 ABCG1 and Wnt-associated genes were significantly upregulated. Upregulation of ABCG1 and oxaliplatin resistance were associated with activation of Wnt signaling. Interference with ABCG1 expression or inhibition of Wnt signaling resulted in reversal of the saracatinib-induced oxaliplatin resistance in the HCC cell lines. Conclusions: These studies demonstrated that combined or sequential chemotherapy with oxaliplatin and saracatinib reduced antitumor efficacy, and this antagonism was attributed to the upregulation of ABCG1 and activation of Wnt signaling pathway by saracatinib.

2019-03-30 | GSE129071 | GEO

Oxaliplatin resistance is enhanced by saracatinib via upregulation Wnt-ABCG1 signaling in hepatocellular carcinoma.

Project description: Not available

| S-EPMC6958774 | biostudies-literature

CCN2-MAPK-Id-1 Loop Feedback Amplification is involved in Maintaining Stemness in Oxaliplatin-resistant Hepatocellular Carcinoma

Project description:Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide. Most patients are at an advanced stage at diagnosis, and are not eligible for curative therapy. Chemotherapy is an alternative treatment for advanced HCCs, but resistance is found in many patients. Understanding the underlying mechanisms in chemo-resistance is critical to further improve the efficacy of HCC treatment. In this study, we found that increased expression of Id-1 and CCN2 were closely related to oxaliplatin resistance in HCC. Upregulation of CCN2 and Id-1 was independently associated with shorter survival and increased recurrence in HCC patients, and significantly enhanced oxaliplatin resistance and promoted lung metastasis in vivo, whereas knock-down of their expression significantly reversed the chemo-resistance and inhibited HCC cell stemness. cDNA microarrays and PCR revealed that Id-1 and MAPK pathway were the downstream signaling of CCN2, and Id-1 could upregulate CCN2 in a positive feedback manner. Moreover, CCN2 significantly enhanced oxaliplatin resistance by activating the MAPK signaling pathway and upregulating Id-1 expression. Meanwhile, MAPK/Id-1 signaling was demonstrated as one of the most important autocrine signaling pathways regulated by CCN2 in oxaliplatin-resistant models, and combination with sorafenib could improve the efficacy of oxaliplatin in HCC. Conclusions: These findings suggest that CCN2-MAPK-Id-1 loop feedback amplification is involved in oxaliplatin-resistant HCC, and the combination of oxaliplatin with inhibitor of CCN2 or MAPK signaling could provide a promising approach to ameliorating HCC progression and oxaliplatin resistance.

2019-01-02 | GSE124529 | GEO

SILAC-Based Quantitative Proteomics Identifies Multifactorial Mechanism of Oxaliplatin Resistance in Pancreatic Cancer Cells

Project description:Oxaliplatin is a commonly used chemotherapeutic drug for the treatment of pancreatic cancer. Understanding the cellular mechanisms of oxaliplatin resistance is important for developing new strategies to overcome drug resistance in pancreatic cancer. In this study, we performed a stable isotope labelling by amino acids in cell culture (SILAC)-based quantitative proteomics analysis of oxaliplatin-resistant and sensitive pancreatic cancer PANC-1 cells. We identified 107 proteins whose expression levels changed between oxaliplatin-resistant and sensitive cells, which were involved in multiple biological processes, including DNA repair, drug response, apoptotic signalling, and the type 1 interferon signalling pathway. Notably, myristoylated alanine-rich C-kinase substrate (MARCKS) and wntless homolog protein (WLS) were upregulated in oxaliplatin-resistant cells compared to sensitive cells, as confirmed by qRT-PCR and Western blot analysis. We further demonstrated the activation of AKT and β-catenin signalling (downstream targets of MARCKS and WLS, respectively) in oxaliplatin-resistant PANC-1 cells. Additionally, we show that the siRNA-mediated suppression of both MARCKS and WLS enhanced oxaliplatin sensitivity in oxaliplatin-resistant PANC-1 cells. Taken together, our results provide insights into multiple mechanisms of oxaliplatin resistance in pancreatic cancer cells and reveal that MARCKS and WLS might be involved in the chemotherapeutic resistance in pancreatic cancer.

2021-09-09 | PXD021251 | Pride

Oncogenic Serine-Threonine Kinase Receptor Associated Protein Supports Hepatocellular Carcinoma Cell Growth by Enhancing Wnt/β-catenin Signaling

Project description:Serine-threonine kinase receptor-associated protein (STRAP) is upregulated in breast, colorectal and lung cancers, promoting their growth. We identify the upregulation of STRAP in hepatocellular carcinomas. Elevated STRAP endows tumor cells with growth advantage by reprograming a variety of metabolic processes and signaling pathways critical for hepatocellular carcinoma progression. Especially, enhanced Wnt/β-catenin signaling is likely to be a major effector of its tumor-promoting role.

2018-09-03 | GSE101061 | GEO

Differentially expressed genes between oxaliplatin-resistant and oxaliplatin-non-resistant patient samples [Clinical samples-RNA-seq]

Project description:To identify key drivers of oxaliplatin resistance, we collected and analyzed the DEGs between oxaliplatin-resistant and oxaliplatin-non-resistant patient samples

2023-02-28 | GSE206501 | GEO

Gene expression profiles of liver and lung endothelial cells during normal and upregulation of Wnt/beta-catenin signaling

Project description:We genetically overexpressed a gain-of-function beta-catenin allele in liver and lung endothelial cells to identifiy the set of BBB genes regulated by the Wnt/beta-catenin pathway

2018-02-25 | GSE95201 | GEO

Response to oxaliplatin in CCD-18Co

Project description:We obtained the gene expression signature from oxaliplatin-treated fibroblasts and quantified the association of oxaliplatin-activated fibroblasts with disease progression in colorectal cancer.

2023-01-16 | GSE181020 | GEO

Neddylation is Essential for beta-catenin Degradation in Wnt Signaling Pathway

Project description:Mass spectrometry profiling of beta-catenin co-immunoprecipitation proteins from MLN treated HEK293T cells

2022-01-27 | PXD031303 | iProX

Beta-catenin target genes in colorectal carcinoma cell lines with deregulated Wnt/beta-catenin signaling

Project description:To validate the suitability of two commonly used colorectal cancer cell lines, DLD1 and SW480, as model systems to study colorectal carcinogenesis, we treated these cell lines with beta-catenin siRNA and identified beta-catenin target genes using DNA microarrays. The list of identified target genes was compared to previously published beta-catenin target genes found in the PubMed and the GEO databases. Based on the large number of beta-catenin target genes found to be similarly regulated in DLD1, SW480 and LS174T as well as the large overlap with confirmed β-catenin target genes, we conclude that DLD1 and SW480 colon carcinoma cell lines are suitable model systems to study beta-catenin regulated genes and signaling pathways 12 arrays (2 cell lines, 2 treatments, 3 biological replicates)

2013-12-31 | E-GEOD-44097 | biostudies-arrayexpress

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