Endogenous protein S100A14 stabilizes glutaminase to render hepatocellular carcinoma resistant to sorafenib
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ABSTRACT:
PROVIDER: PRJNA1187621 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR31386822_1.fastq.gz | Fastqsanger.gz | |||
| SRR31386822_2.fastq.gz | Fastqsanger.gz | |||
| SRR31386823_1.fastq.gz | Fastqsanger.gz | |||
| SRR31386823_2.fastq.gz | Fastqsanger.gz |
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Project description:Many cases of advanced hepatocellular carcinoma (HCC) are resistant to the widely used drug sorafenib, which worsens prognosis. While many studies have explored how acquired resistance emerges during drug exposure, the mechanism underlying primary resistance before treatment still remain elusive. Here, we performed single-cell lineage tracing and RNA sequencing to identify sorafenib-resistant lineages in HCC, and demonstrated that high expression of S100A14 was positively associated with primary sorafenib resistance. Knocking down S100A14 rendered xenograft tumors in mice significantly more sensitive to sorafenib. Mechanistic studies indicated that S100A14 binds to glutaminase and blocks its phosphorylation at residues Y308 and S314, which in turn inhibits its ubiquitination and subsequent degradation. This stabilization of glutaminase reduces oxidative stress in HCC cells and thereby antagonizes the ability of sorafenib to induce apoptosis. Inhibiting glutaminase with telaglenastat (CB-839) significantly improved sorafenib efficacy against xenograft tumors in vivo. These results suggest that S100A14 can contribute to primary sorafenib resistance in HCC by stabilizing glutaminase. Thus, analyzing the expression of S100A14 may be useful for predicting primary sorafenib resistance, and inhibiting S100A14 or glutaminase may be effective for preventing or overcoming such resistance.
2025-03-02 | GSE282234 | GEO
Project description:Sorafenib resistance up-regulated circRNA_104797 could be transmitted by exosomes and responsible for the spread of Sorafenib resistance among HCC cells. CircRNA_104797 was critical for Sorafenib resistance maintenance and silencing circRNA_104797 could substantially increase the efficacy of Sorafenib by inducing apoptosis. Mechanism dissection unveiled that circRNA_104797 could specifically sponge miR-103a-2-5p and miR-660-3p and act as a competing endogenous RNA (ceRNA), thus competitively activated wnt/β-catenin pathway and induced Sorafenib resistance. Meanwhile, LC-MS/MS also revealed that circRNA_104797 could specifically bind to translation related proteins, which might regulate downstream glycan biosynthesis and lipid metabolism, and finally induce Sorafenib resistance. In vivo experiments portrayed a promising clinical application by locally injection of in vivo-grade siRNA for circRNA_104797 by TACE or other manners, which could intensively enhance Sorafenib efficacy in HCC patients. The clinical application of in vivo-grade siRNA for circRNA_104797 in Sorafenib treated HCC patients might shed bright future for the management of advanced HCC.
2020-07-25 | GSE101850 | GEO
Project description:The decline in sperm function is a major cause of human male infertility. Glutaminase, a mitochondrial enzyme that catalyzes the hydrolysis of glutamine to generate glutamate, takes part in many diverse biological processes such as neurotransmission, metabolism, and cellular senescence. Here we report a role of glutaminase in regulating sperm function. By generating a triple mutant that harbors a loss-of-function allele for each of all three mammalian glutaminase orthologs, we found that glutaminase gene activity is required for optimal C. elegans sperm function. Tissue-specific gene manipulations showed that germline glutaminase activity plays an important role. Moreover, transcriptional profiling and antioxidant treatment suggested that glutaminase promotes sperm function by maintaining cellular redox homeostasis. As maintaining a low level of ROS is crucial to human sperm function, it is very likely that glutaminase plays a similar role in humans and therefore can be a potential target for treating human male infertility.
2023-02-15 | GSE224117 | GEO
Project description:DPP9 Stabilizes NRF2 to Suppress Ferroptosis and Induce Sorafenib Resistance in Clear Cell Renal Cell Carcinoma
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Project description:Understanding the mechanisms underlying evasive resistance in cancer is an unmet medical need to improve the efficacy of current therapies. In hepatocellular carcinoma (HCC), aberrant expression of hypoxia inducible factor 1 a (HIF1a) and increased aerobic glycolysis metabolism represent drivers of the development of resistance to therapy with the multi-kinase inhibitor Sorafenib. However, it has remained unknown how HIF1a is activated and how its activity and the subsequent induction of aerobic glycolysis promotes Sorafenib resistance in HCC. Here, we report the ubiquitin-specific peptidase USP29 as a new regulator of HIF1a and of aerobic glycolysis during the development of Sorafenib resistance in HCC. In particular, we have identified USP29 as a critical deubiquitylase (DUB) of HIF1a, which directly deubiquitinates and stabilizes HIF1a and, thus, promotes its transcriptional activity. Among the transcriptional targets of HIF1a is the gene encoding for hexokinase 2 (HK2), a key enzyme of the glycolytic pathway. The absence of USP29, and thus of HIF1a transcriptional activity, reduces the levels of aerobic glycolysis and reinstalls the sensitivity to Sorafenib treatment in Sorafenib-resistant HCC cells in vitro and in xenograft transplantation mouse models in vivo. Notably, the absence of USP29 and high HK2 expression levels correlate with the response of HCC patients to Sorafenib therapy. Together, the data demonstrate that, as a DUB of HIF1a, USP29 promotes Sorafenib resistance in HCC cells by upregulating glycolysis, thereby opening new avenues for therapeutically targeting Sorafenib-resistant HCC in patients.
2021-07-27 | GSE158458 | GEO
Project description:We used an expression profiling chip to detect the expression profile of PLC cells after they were treated with sorafenib and sorafenib probe
2018-12-12 | GSE123600 | GEO
Project description:Sorafenib is associated with cardiac adverse effects, including left ventricular dysfunction. However, the precise mechanism remains unclear. Here, we aimed to establish the genes responsible for this cardiotoxicity using zebrafish. A pigmentless zebrafish line expressing green fluorescent protein in the heart were treated with or without sorafenib. In vivo fluorescent cardiac imaging revealed that the ventricular dimension of the longitudinal axis in zebrafish treated with sorafenib was significantly lower than in those without sorafenib. Transcriptome analysis of zebrafish hearts revealed that expression of stanniocalcin1 (stc1) in zebrafish treated with sorafenib was significantly lower than that without sorafenib treatment. We were able to demonstrate that the ventricular dimension of the longitudinal axis in stc1 morphant was significantly smaller than that of control zebrafish and that forced expression of stc1 normalized the decrease in ventricular diameter in stc1 morphant and zebrafish treated with sorafenib. These data suggest that stc1 is the gene responsible for sorafenib-induced cardiotoxicity. Gene expression regulated by sorafenib in zebrafish at 4 dpf was measured. Four independent experiments were performed for each group.
2014-12-04 | E-GEOD-61155 | biostudies-arrayexpress
Project description:Sorafenib is a first-line chemotherapy drug for treating advanced hepatocellular carcinoma (HCC). However, its therapeutic effect has been seriously affected by the emergence of sorafenib resistance in HCC patients. The underlying mechanism of sorafenib resistance is unclear. Here, we report a circular RNA, cDCBLD2, which plays an important role in sorafenib resistance in HCC. We found that cDCBLD2 was upregulated in sorafenib-resistant (SR) HCC cells, and knocking down cDCBLD2 expression could significantly increase sorafenib-related cytotoxicity. Further evidence showed that cDCBLD2 can bind to microRNA (miR)-345-5p through a competing endogenous RNA mechanism, increase type IIA topoisomerase (TOP2A) mRNA stability through a miRNA sponge mechanism, and reduce the effects of sorafenib treatment on HCC by inhibiting apoptosis. Our findings also suggest that miR-345-5p can negatively regulate TOP2A levels by binding to the coding sequence region of its mRNA. Additionally, targeting cDCBLD2 by injecting a specific small interfering RNA (siRNA) could significantly overcome sorafenib resistance in a patient-derived xenograft (PDX) mouse model of HCC. Taken together, our study provides a proof-of-concept for a potential strategy to overcome sorafenib resistance in HCC patients by targeting cDCBLD2 or TOP2A.
2023-12-11 | GSE240109 | GEO
Project description:sorafenib is the treatment of reference for hepatocellular carcinoma (HCC). We applied sorafenib on the human HCC cell line Huh7 and the subclone shRb, carrying a stable knock-down of the expression of the RB1 gene, a key regulator of liver carcinogenesis. Our aim was to better understand the physiologic and metabolic consequences of the exposure of HCC cells to sorafenib. We used microarrays to detail the global programme of gene expression at an early time point (9h) after exposure to sorafenib Whole-genome microarrays were used to study the transcriptome of Huh7 cells exposed to Sorafenib
2016-06-30 | E-GEOD-75620 | biostudies-arrayexpress
Project description:Sorafenib is associated with cardiac adverse effects, including left ventricular dysfunction. However, the precise mechanism remains unclear. Here, we aimed to establish the genes responsible for this cardiotoxicity using zebrafish. A pigmentless zebrafish line expressing green fluorescent protein in the heart were treated with or without sorafenib. In vivo fluorescent cardiac imaging revealed that the ventricular dimension of the longitudinal axis in zebrafish treated with sorafenib was significantly lower than in those without sorafenib. Transcriptome analysis of zebrafish hearts revealed that expression of stanniocalcin1 (stc1) in zebrafish treated with sorafenib was significantly lower than that without sorafenib treatment. We were able to demonstrate that the ventricular dimension of the longitudinal axis in stc1 morphant was significantly smaller than that of control zebrafish and that forced expression of stc1 normalized the decrease in ventricular diameter in stc1 morphant and zebrafish treated with sorafenib. These data suggest that stc1 is the gene responsible for sorafenib-induced cardiotoxicity.
2014-12-04 | GSE61155 | GEO