Owing to the recent emergence of drug resistance to Bruton’s tyrosine kinase inhibitors (BTK) in chronic lymphocytic leukemia (CLL) treatment, it is crucial to identify alternative therapeutic targets. Therefore, we aimed to identify therapeutic options for CLL besides BTK. We identified that HIF1A expression was higher in CLL patients than in controls, which may suggest good prognosis. We used a lentiviral knockdown of EGLN1 (encoding hypoxia-inducible factor prolyl hydroxylase [HIF-PH]) and found that the growth of MEC-1 cells slowed in the knockdown group. Treatment of CLL cell lines MEC-1 and HG3 with the HIF-PH inhibitor molidustat showed that molidustat could induce apoptosis in a concentration-dependent manner in CLL cells and had low cytotoxicity at this concentration. CXCR4, HIF1A, SLC2AI, and VEGF, the downstream molecules of the HIF pathway, were upregulated after molidustat treatment. Western blotting results indicated that molidustat increased HIF1A expression in CLL cell lines and cells from CLL patients, and sequencing/quantitative PCR analysis demonstrated that the ribosome biogenesis pathway was inhibited in MEC-1 cells after molidustat treatment. We further identified synergistic cytotoxicity of molidustat in combination with ibrutinib on the MEC-1 and HG3 cell lines at certain concentrations. Therefore, molidustat is a potential therapeutic option for CLL.
Hepatocellular carcinoma (HCC) is one of the most prevalent tumors worldwide and the leading contributor to cancer-related deaths. The progression and metastasis of HCC are closely associated with altered mitochondrial metabolism, including mitochondrial stress response. Mitokines, soluble proteins produced and secreted in response to mitochondrial stress, play an essential immunomodulatory role. Immunotherapy has emerged as a crucial treatment option for HCC. However, a positive response to therapy is typically dependent on the interaction of tumor cells with immune regulation within the tumor microenvironment. Therefore, exploring the specific immunomodulatory mechanisms of mitokines in HCC is essential for improving the efficacy of immunotherapy. This study provides a comprehensive overview of the association between HCC and the immune microenvironment and highlights recent progress in understanding the involvement of mitochondrial function in preserving liver function. In addition, a systematic review of mitokines-mediated immunomodulation in HCC is presented. Finally, the potential diagnostic and therapeutic roles of mitokines in HCC are prospected and summarized. Recent progress in mitokine research represents a new prospect for mitochondrial therapy. Considering the potential of mitokines to regulate immune function, investigating them as a relevant molecular target holds great promise for the diagnosis and treatment of HCC.
Background and Aims The growing knowledge of ferroptosis has suggested the regulatory role of ferroptosis in hepatocellular carcinoma (HCC), but the pertinent molecular mechanisms remain unclear. Herein, this study investigated the mechanistic basis of ferroptosis-related genes (ferrGenes) in the growth of HCC. Methods Differentially expressed human ferrGenes and tumor-related transcription factors (TFs) were obtained from the The Cancer Genome Atlas (TCGA) dataset and the GTEx dataset. Spearman method-based correlation analysis were conducted to construct TF-ferrGene coexpression regulatory network. Key genes associated with prognosis were singled out with Lasso regression and multivariate Cox analysis to construct the prognostic risk model. Then the accuracy and independent prognostic ability of the model were evaluated. Expression of CENPA and STMN1 was determined in clinical HCC tissues and HCC cells, and their binding was analyzed with dual-luciferase and chromatin immunoprecipitation (ChIP) assays. Furthermore, ectopic expression and knockdown assays were performed in HCC cells to assess the effect of CENPA and STMN1 on ferroptosis and malignant phenotypes. Results The prognostic risk model constructed based on the eight TF-ferrGene regulatory network-related genes accurately predicted the prognosis of HCC patients. It was strongly related to the clinical characteristics of HCC patients. Moreover, CENPA/STMN1 might be a key TF-ferrGene regulatory network in ferroptosis of HCC. CENPA and STMN1 were overexpressed in HCC tissues and cells. Additionally, CENPA facilitated STMN1 transcription by binding to STMN1 promoter, thus facilitating the malignant phenotypes and suppressing the ferroptosis of HCC cells. Conclusions Taken together, CENPA curbs the ferroptosis of HCC cells by upregulating STMN1 transcription, thereby promoting HCC growth.
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