<scp>SPI1</scp> involvement in malignant melanoma pathogenesis by regulation of <scp>HK2</scp> through the <scp>AKT1</scp>/<scp>mTOR</scp> pathway

Qiu, Xiujuan; Gao, Jun; Gong, Zhifan; Zhao, Xiaogang; Luo, Haichao; Geng, Xuerui

doi:10.1111/jcmm.17844

Cited by 5 publications

(1 citation statement)

References 26 publications

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“…Recent studies underscore the pivotal role of the mTOR pathway in oncogenesis, suggesting its broad implications across various cancers. 22 , 23 , 24 These investigations reveal enhanced mTOR signalling in tumour environments, promoting proliferation and survival, a finding consistent with the mechanistic pathways observed in HBV‐related HCC. 25 , 26 This convergence of evidence supports the hypothesis that HBV infection directly modulates mTOR signalling, suggesting a targeted approach for therapeutic intervention.…”

Section: Discussionsupporting

confidence: 79%

SOD1 inhibition enhances sorafenib efficacy in HBV‐related hepatocellular carcinoma by modulating PI3K/Akt/mTOR pathway and ROS‐mediated cell death

Lee,

Kim,

Lee

et al. 2024

J Cellular Molecular Medi

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Hepatitis B Virus (HBV) infection significantly elevates the risk of hepatocellular carcinoma (HCC), with the HBV X protein (HBx) playing a crucial role in cancer progression. Sorafenib, the primary therapy for advanced HCC, shows limited effectiveness in HBV‐infected patients due to HBx‐related resistance. Numerous studies have explored combination therapies to overcome this resistance. Sodium diethyldithiocarbamate (DDC), known for its anticancer effects and its inhibition of superoxide dismutase 1 (SOD1), is hypothesized to counteract sorafenib (SF) resistance in HBV‐positive HCCs. Our research demonstrates that combining DDC with SF significantly reduces HBx and SOD1 expressions in HBV‐positive HCC cells and human tissues. This combination therapy disrupts the PI3K/Akt/mTOR signalling pathway and promotes apoptosis by increasing reactive oxygen species (ROS) levels. These cellular changes lead to reduced tumour viability and enhanced sensitivity to SF, as evidenced by the synergistic suppression of tumour growth in xenograft models. Additionally, DDC‐mediated suppression of SOD1 further enhances SF sensitivity in HBV‐positive HCC cells and xenografted animals, thereby inhibiting cancer progression more effectively. These findings suggest that the DDC‐SF combination could serve as a promising strategy for overcoming SF resistance in HBV‐related HCC, potentially optimizing therapy outcomes.

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Section: Discussionsupporting

confidence: 79%

SOD1 inhibition enhances sorafenib efficacy in HBV‐related hepatocellular carcinoma by modulating PI3K/Akt/mTOR pathway and ROS‐mediated cell death

Lee,

Kim,

Lee

et al. 2024

J Cellular Molecular Medi

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The Role of ATP Synthase Subunit e (ATP5I) in Mediating the Metabolic and Antiproliferative Effects of Biguanides

Lefrançois,

Lavallée,

Rowell

et al. 2024

Preprint

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Here we identify the subunit e of F1Fo-ATP synthase (ATP5I) as a target of medicinal biguanides. ATP5I maintains the stability of F1Fo-ATP synthase dimers which is crucial for shaping cristae morphology. Although its roles have been mainly studied in yeast models, its function in cellular energy metabolism within the context of cancer remains poorly characterized. In this study, we demonstrate that ATP5I interacts with a biguanide analoguein vitroand disabling its expression by CRISPR-Cas9 in pancreatic cancer cells leads to the same phenotype as biguanide treated cells including a decrease in the levels of some respiratory complex subunits, mitochondrial morphology alterations, inhibition of oxidative phosphorylation (OXPHOS) and a compensatory increase in glycolysis. Moreover, ATP5I knockout (KO) cells exhibit resistance to the antiproliferative effects of biguanides, but reintroduction of ATP5I rescues the metabolic and anti-proliferative effects of metformin and phenformin. These findings highlight ATP5I as a significant antineoplastic mitochondrial target of medicinal biguanides, opening new opportunities for the development of mitochondrial-targeted therapies.

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Exploring the Role of Neutrophil-Related Genes in Osteosarcoma via an Integrative Analysis of Single-Cell and Bulk Transcriptome

Lu,

Rui,

et al. 2024

Biomedicines

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Background: The involvement of neutrophil-related genes (NRGs) in patients with osteosarcoma (OS) has not been adequately explored. In this study, we aimed to examine the association between NRGs and the prognosis as well as the tumor microenvironment of OS. Methods: The OS data were obtained from the TARGET-OS and GEO database. Initially, we extracted NRGs by intersecting 538 NRGs from single-cell RNA sequencing (scRNA-seq) data between aneuploid and diploid groups, as well as 161 up-regulated differentially expressed genes (DEGs) from the TARGET-OS datasets. Subsequently, we conducted Least Absolute Shrinkage and Selection Operator (Lasso) analyses to identify the hub genes for constructing the NRG-score and NRG-signature. To assess the prognostic value of the NRG signatures in OS, we performed Kaplan–Meier analysis and generated time-dependent receiver operating characteristic (ROC) curves. Gene enrichment analysis (GSEA) and gene set variation analysis (GSVA) were utilized to ascertain the presence of tumor immune microenvironments (TIMEs) and immunomodulators (IMs). Additionally, the KEGG neutrophil signaling pathway was evaluated using ssGSEA. Subsequently, PCR and IHC were conducted to validate the expression of hub genes and transcription factors (TFs) in K7M2-induced OS mice. Results: FCER1G and C3AR1 have been identified as prognostic biomarkers for overall survival. The findings indicate a significantly improved prognosis for OS patients. The effectiveness and precision of the NRG signature in prognosticating OS patients were validated through survival ROC curves and an external validation dataset. The results clearly demonstrate that patients with elevated NRG scores exhibit decreased levels of immunomodulators, stromal score, immune score, ESTIMATE score, and infiltrating immune cell populations. Furthermore, our findings substantiate the potential role of SPI1 as a transcription factor in the regulation of the two central genes involved in osteosarcoma development. Moreover, our analysis unveiled a significant correlation and activation of the KEGG neutrophil signaling pathway with FCER1G and C3AR1. Notably, PCR and IHC demonstrated a significantly higher expression of C3AR1, FCER1G, and SPI1 in Balb/c mice induced with K7M2. Conclusions: Our research emphasizes the significant contribution of neutrophils within the TIME of osteosarcoma. The newly developed NRG signature could serve as a good instrument for evaluating the prognosis and therapeutic approach for OS.

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SPI1 involvement in malignant melanoma pathogenesis by regulation of HK2 through the AKT1/mTOR pathway

Cited by 5 publications

References 26 publications

SOD1 inhibition enhances sorafenib efficacy in HBV‐related hepatocellular carcinoma by modulating PI3K/Akt/mTOR pathway and ROS‐mediated cell death

SOD1 inhibition enhances sorafenib efficacy in HBV‐related hepatocellular carcinoma by modulating PI3K/Akt/mTOR pathway and ROS‐mediated cell death

The Role of ATP Synthase Subunit e (ATP5I) in Mediating the Metabolic and Antiproliferative Effects of Biguanides

Exploring the Role of Neutrophil-Related Genes in Osteosarcoma via an Integrative Analysis of Single-Cell and Bulk Transcriptome

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