bims-glucam 2023-12-10 papers

Issue of 2023‒12‒10
five papers selected by
Sreeparna Banerjee, Middle East Technical University

Am J Cancer Res. 2023 ;13(11): 5289-5305

IGF2BP3-mediated regulation of GLS and GLUD1 gene expression promotes treg-induced immune escape in human cervical cancer.

Tiantian Zhou, Ziyi Xiao, Jin Lu, Lihua Zhang, Le Bo, Jinhua Wang.

This study aimed to investigate the impact of IGF2BP3, a well-known m6A modification-related protein, on the metabolic and immune microenvironment of human cervical cancer. Bioinformatics analysis was performed to analyze the expression of IGF2BP3 in various databases, and its findings were validated using human cervical cancer tissue microarrays. We conducted a study to investigate the impact of IGF2BP3 on glutamine metabolism in cervical cancer cells through the application of metabolomics and metabolic flow analysis. Additionally, we explored how cervical cancer cells promote immune escape by secreting glutamine-derived lactate in a 3D culture setting. To identify the specific targets of IGF2BP3 that influence glutamine metabolism in cervical cancer, we employed RIP-seq analysis. IGF2BP3 exhibited high expression levels in multiple cervical cancer datasets, and its expression was significantly associated with the prognosis of cervical cancer patients. In mixed 3D cell cultures of cervical cancer and T cells, IGF2BP3 was found to enhance glutamate and glutamine metabolism in cervical cancer cells by up regulating the expression of GLS and GLUD1 genes. Moreover, it influenced the differentiation of Treg cells by promoting lactate production and secretion in cervical cancer, leading to immune escape. Mechanistic analysis revealed that IGF2BP3 stabilized the mRNA of GLS and GLUD1 genes through m6A modification, thereby facilitating glutamate and glutamine metabolism in cervical cancer cells and regulating lactate production. Additionally, we investigated the correlation between GLS, GLUD1 protein expression, and IGF2BP3 expression in human cervical cancer through multicolor immunofluorescence staining. The relevance of IGF2BP3 in the context of Treg cell-associated immune escape in cervical cancer was also confirmed. IGF2BP3 exhibits high expression in human cervical cancer and plays a crucial role in stabilizing the mRNA of GLS and GLUD1 genes, key metabolic enzymes in glutamate and glutamine metabolism, through m6A modification. This process leads to immune escape in cervical cancer by promoting lactate production and secretion.

Keywords: IGF2BP3; M6A modification; cervical cancer; glutamine metabolism

Discov Med. 2023 Dec;35(179): 995-1014

LncRNA SLC1A5-AS/MZF1/ASCT2 Axis Contributes to Malignant Progression of Hepatocellular Carcinoma.

Jiawen Jiang, Wei Dong, Wen Zhang, Qian Wang, Ruyi Wang, Jiaxu Wang, Hao Wu, Hui Dong, Robert Chunhua Zhao, Jiao Wang, Zhe Li.

BACKGROUND: Hypoxia is a pivotal factor influencing cellular gene expression and contributing to the malignant progression of tumors. Metabolic anomalies under hypoxic conditions are predominantly mediated by mitochondria. Nonetheless, the exploration of hypoxia-induced long noncoding RNAs (lncRNAs) associated with mitochondria remains largely uncharted.METHODS: We established hypoxia cell models using primary human hepatocytes (PHH) and hepatocellular carcinoma (HCC) cell lines. We isolated mitochondria for high-throughput sequencing to investigate the roles of candidate lncRNAs in HCC progression. We employed in vitro and in vivo assays to evaluate the functions of solute carrier family 1 member 5 antisense lncRNA (SLC1A5-AS). RNA-seq was utilized to scrutinize the comprehensive genome profile regulated by SLC1A5-AS in HCC. Subsequently, quantitative real-time polymerase chain reaction (qRT-PCR) and western blot analysis were utilized to validate the expression of alanine-serine-cysteine transporter 2 (ASCT2, encoded by the SLC1A5 gene), and a glutamine uptake assay was employed to estimate the glutamine uptake capacity of Huh-7 cells after SLC1A5-AS overexpression. To delve into the mechanisms governing the regulation of SLC1A5 expression by SLC1A5-AS, we employed a biotin-labeled SLC1A5-AS probe in conjunction with a western blot assay to confirm the interactions between SLC1A5-AS and candidate transcription factors. Luciferase reporter assays and chromatin immunoprecipitation (ChIP) were utilized to authenticate the effects of the predicted transcription factors on SLC1A5 promoter activity.
RESULTS: Following the screening, we identified CTB-147N14.6, derived from the antisense strand of the SLC1A5 gene, which we have named SLC1A5-AS. SLC1A5-AS exhibited significantly elevated expression levels in HCC tissue and was associated with poor prognosis in HCC patients. In vitro and in vivo assays revealed that the overexpression of SLC1A5-AS significantly heightened cell invasion and metastasis. RNA-seq data unveiled SLC1A5-AS involvement in glutamine metabolism, left-handed amino (L-amino) acid transmembrane transporter activity, and the nuclear factor kappa-B (NF-κB) signaling pathway. Overexpression of SLC1A5-AS markedly increased ASCT2 mRNA/protein levels, thereby enhancing glutamine uptake and promoting the growth and metastasis of HCC cells. Mechanistically, higher RNA levels of SLC1A5-AS directly bound with myeloid zinc finger 1 (MZF1), acting as a transcriptional repressor, thus diminishing its binding to the SLC1A5 promoter region.
CONCLUSIONS: Our findings unveil a novel role for the lncRNA SLC1A5-AS in glutamine metabolism, suggesting that targeting SLC1A5-AS/MZF1, in conjunction with ASCT2 inhibitor treatment, could be a potential therapeutic strategy for this disease.

Keywords: glutamine metabolism; hepatocellular carcinoma; hypoxia; lncRNA SLC1A5-AS/MZF1/ASCT2

DOI: https://doi.org/10.24976/Discov.Med.202335179.96

bioRxiv. 2023 Nov 30. pii: 2023.11.21.568200. [Epub ahead of print]

Systems levels analysis of lipid metabolism in oxygen-induced retinopathy.

Charandeep Singh.

Hyperoxia induces glutamine-fueled anaplerosis in the Muller cells, endothelial cells, and retinal explants. Anaplerosis takes away glutamine from the biosynthetic pathway to the energy-producing TCA cycle. This process depletes biosynthetic precursors from newly proliferating endothelial cells. The induction of anaplerosis in the hyperoxic retina is a compensatory response, either to decreased glycolysis or decreased flux from glycolysis to the TCA cycle. We hypothesized that by providing substrates that feed into TCA, we could reverse or prevent glutamine-fueled anaplerosis, thereby abating the glutamine wastage for energy generation. Using an oxygen-induced retinopathy (OIR) mouse model, we first compared the difference in fatty acid metabolism between OIR-resistant BALB/cByJ and OIR susceptible C57BL/6J strains to understand if these strains exhibit metabolic difference that protects BALB/cByJ from the hyperoxic conditions and prevents their vasculature in oxygen-induced retinopathy model. Based on our findings from the metabolic comparison between two mouse strains, we hypothesized that the medium-chain fatty acid, octanoate, can feed into the TCA and serve as an alternative energy source in response to hyperoxia. Our systems levels analysis of OIR model shows that the medium chain fatty acid can serve as an alternative source to feed TCA. We here, for the first time, demonstrate that the retina can use medium-chain fatty acid octanoate to replenish TCA in normoxic and at a higher rate in hyperoxic conditions.

DOI: https://doi.org/10.1101/2023.11.21.568200

IUBMB Life. 2023 Dec 06.

Amino acid deprivation induces TXNIP expression by NRF2 downregulation.

Se Hee Ahn, Se-Kyeong Jang, Yu Jin Kim, Gyeongmi Kim, Ki Soo Park, In-Chul Park, Hyeon-Ok Jin.

Thioredoxin-interacting protein (TXNIP) is sensitive to oxidative stress and is involved in the pathogenesis of various metabolic, cardiovascular, and neurodegenerative disorders. Therefore, several studies have suggested that TXNIP is a promising therapeutic target for several diseases, particularly cancer and diabetes. However, the regulation of TXNIP expression under amino acid (AA)-restricted conditions is not well understood. In the present study, we demonstrated that TXNIP expression was promoted by the deprivation of AAs, especially arginine, glutamine, lysine, and methionine, in non-small cell lung cancer (NSCLC) cells. Interestingly, we determined that increased TXNIP expression induced by AA deprivation was associated with nuclear factor erythroid 2-related factor 2 (NRF2) downregulation, but not with activating transcription factor 4 (ATF4) activation. Furthermore, N-acetyl-l-cysteine (NAC), a scavenger of reactive oxygen species (ROS), suppressed TXNIP expression in NSCLC cells deprived of AA. Collectively, the induction of TXNIP expression by AA deprivation was mediated by ROS production, potentially through NRF2 downregulation. Our findings suggest that TXNIP expression may be associated with the redox homeostasis of AA metabolism and provide a possible rationale for a therapeutic strategy to treat cancer with AA restriction.

Keywords: amino acid deprivation; non-small cell lung cancer; nuclear factor erythroid 2-related factor 2; reactive oxygen species; thioredoxin-interacting protein

DOI: https://doi.org/10.1002/iub.2792

Curr Opin Biotechnol. 2023 Dec 05. pii: S0958-1669(23)00132-5. [Epub ahead of print]85 103022

The posttranslational regulation of amino acid transporters is critical for their function in the tumor microenvironment.

Jessica C Koe, Seth J Parker.

Amino acid transporters (AATs) facilitate nutrient uptake and nutrient exchange between cancer and stromal cells. The posttranslational modification (PTM) of transporters is an important mechanism that tumor-associated cells use to dynamically regulate their function and stability in response to microenvironmental cues. In this review, we summarize recent findings that demonstrate the significance of N-glycosylation, phosphorylation, and ubiquitylation for the function of AATs. We also highlight powerful approaches that hijack the PTM machinery that could be used as therapeutics or tools to modulate transporter activity.

DOI: https://doi.org/10.1016/j.copbio.2023.103022