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USP18-mediated NCOA4 deISGylation and ferroptosis inhibition drives targeted therapy resistance in hepatocellular carcinoma

ABSTRACT: To elucidate the principal downstream mediator responsible for USP18-mediated Sorafenib resistance in HCC, we conducted cluster analysis on the differential protein expression based on the whole-proteome analysis of HepG2 cells with or without overexpression of USP18 (HepG2-USP18-OE vs. HepG2-Ctrl), we identified 47 commonly downregulated proteins and 31 upregulated proteins .

ORGANISM(S): Homo Sapiens

SUBMITTER: Hao Zhang

PROVIDER: PXD047888 | iProX | Sun Dec 17 00:00:00 GMT 2023

REPOSITORIES: iProX

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Project description:Molecular targeted therapy has shown promise as a treatment for advanced hepatocellular carcinoma (HCC). Sorafenib, a multikinase inhibitor, recently received FDA approval for the treatment of advanced HCC. However, although sorafenib is well tolerated, concern for its safety has been expressed. Celecoxib (CelebrexM-BM-.) is a selective cyclooxygenase-2 (COX-2) inhibitor wich exhibits antitumor effects in human HCC cells. The present study examined the interaction between celecoxib and sorafenib in two human liver tumor cell lines HepG2 and Huh7. Our data showed that each inhibitor reduced cell growth and the combination of celecoxib with sorafenib synergistically inhibited cell growth and increased apoptosis. To better understand the molecular mechanisms underlying the synergistic antitumor activity of combination, we investigated the expression profile of the combination-treated liver cancer cell lines, using microarray analysis. Combination treatment significantly altered expression levels of 1,986 and 2,483 transcripts in HepG2 and Huh7 cells, respectively. Genes, functionally involved in cell death, signal transduction and regulation of transcription were predominantly up-regulated, while genes implicated in metabolism, cell cycle control and DNA replication and repair were mainly down-regulated upon treatment. However, combination-treated HCC cell line displayed specificity in the expression and activity of crucial factors involved in hepatocarcinogenesis. The altered expression of some of these genes was confirmed by semiquantitative and quantitative RT-PCR and by Western blotting. Many novel genes emerged from our transcriptomics analyses, and further functional analyses may determine whether these genes can serve as potential molecular targets for more effective anti-HCC strategies. To identify new potential mechanisms of combined action of celecoxib and sorafenib, their effects on global gene expression in both cell lines were investigated and compared using the DNA microarray technology. Agilent 44K Human Whole Genome Oligonucleotide Microarrays (containing ~44,000 genes) were used to identify global gene expression changes in the HepG2 and Huh7 hepatocellular carcinoma (HCC) cell lines, following simultaneous treatment with 50 M-BM-5M celecoxib and 7.5 M-BM-5M sorafenib for 48 hours. All microarray experiments (a total of four) were performed in duplicates applying dye-swaps to avoid labeling bias.

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USP18-mediated NCOA4 deISGylation and ferroptosis inhibition drives targeted therapy resistance in hepatocellular carcinoma

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