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Sorafenib-associated translation reprogramming in hepatocellular carcinoma cells

ABSTRACT: Sorafenib (Sfb) is a multikinase inhibitor indicated as an oral first-line chemotherapeutic drug for patients with advanced hepatocellular carcinoma (HCC) that has been shown to increase very modestly life expectancy. We have shown that Sfb inhibits protein synthesis at the level of initiation in cancer cells. However, the global snapshot of mRNA translation following Sorafenib-treatment has not been explored so far. In this study, we performed a genome-wide polysome profiling analysis in Sfb-treated HCC cells and demonstrated that, despite global translation repression, a set of different genes remain efficiently translated or are even translationally induced. We reveal that, in response to Sfb inhibition, translation is tuned by established mRNA cis-acting elements and the corresponding protein factors that recognize them, including DAP5 and ARE-binding proteins. At the level of biological processes, Sfb leads to the translational down-regulation of key cellular activities, such as those related to the mitochondrial metabolism and the collagen synthesis, and the translational up-regulation of pathways associated with the adaptation and survival of cells in response to the Sfb-induced stress. Our findings indicate that Sfb induces an adaptive reprogramming of translation and provide valuable information that can facilitate the analysis of other drugs for the development of novel strategies to optimize Sfb therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE282706 | GEO | 2025/03/18

REPOSITORIES: GEO

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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.

Project description:Sorafenib, an oral multikinase inhibitor, is the only approved agent for the treatment of advanced hepatocellular carcinoma (HCC). However, its benefits is modest, also because its mechanism of action remains elusive, therefore, a better understanding of its molecular action and molecular targets are needed. On the basis of our previous studies, here, we investigated the role of the nuclear protein 1 (NUPR1) in HCC and its role in the context of sorafenib treatment. NUPR1 is a stress-inducible protein over-expressed in different malignancies, however, its role in HCC is not yet fully understood. We found that NUPR1, is over-expressed in 53% of primary human HCC samples. Knockdown of NUPR1 significantly increased cell sensitivity to sorafenib and inhibits cell growth, migration and invasion of HCC cells in vitro and tumorigenicity in vivo. Moreover, NUPR1 silencing influenced expression of target genes RelB and IER3. Unsurprisingly, RelB and IER3 knockdown also inhibited HCC cells viability, growth and migration. By gene expression profiling of HCC cells following stable NUPR1 knockdown, we found that genes functionally involved in cell death and survival, cellular response to therapies, lipid metabolism, cell growth and proliferation, molecular transport and cellular movement were mostly suppressed. Network analysis of dynamic gene expression identified NF-ÎºB and ERK as down-regulated gene nodes, and several genes known to be involved in hepatocarcinogenesis were also suppressed. In addition, we identified Runt-related transcription factor 2 (RUNX2) gene as a NUPR1 down-regulated gene. We also demonstrated that RUNX2 gene silencing inhibited HCC cells viability, growth, migration and increased cell sensitivity to sorafenib. Conclusion: We propose that NUPR1/RELB/IER3/RUNX2 pathway play pivotal role in hepatocarcinogenesis. The identification of NUPR1/RELB/IER3/RUNX2 pathway as a potential therapeutic target may contribute to the development of new treatment strategies for HCC management. To better understand the molecular mechanisms of NUPR1 gene action in ovarian HCC cells, we employed the Agilent Whole Human Genome microarrays, containing ~ 44,000 genes to identify global gene expression changes upon NUPR1 suppression in HCC cells. We compared the gene expression of the previously selected shRNA-mediated NURP1-knockdown Hep3B clone against the corresponding control (ctrl) clone. The microarray experiments were performed in duplicates, as two hybridizations were carried out for the NUPR1-suppressing cell clone against the corresponding control, using a fluorescent dye reversal (dye-swap) technique.

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Sorafenib-associated translation reprogramming in hepatocellular carcinoma cells

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