bims-glucam 2023-07-09 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2023‒07‒09
fourteen papers selected by
Sreeparna Banerjee
Middle East Technical University

Regulation of glucose and glutamine metabolism to overcome cisplatin resistance in intrahepatic cholangiocarcinoma.
CAFs targeted ultrasound-responsive nanodroplets loaded V9302 and GLULsiRNA to inhibit melanoma growth via glutamine metabolic reprogramming and tumor microenvironment remodeling.
SLC38A2 and glutamine signalling in cDC1s dictate anti-tumour immunity.
LncRNA PVT1 Confers Cisplatin Resistance of Esophageal Cancer Cells through Modulating the miR-181a-5p-Glutaminase (GLS) Axis.
Tissue-specific reprogramming of glutamine metabolism maintains tolerance to sepsis.
Targeting CXCR1 alleviates hyperoxia-induced lung injury through promoting glutamine metabolism.
Pyruvate transamination and NAD biosynthesis enable proliferation of succinate dehydrogenase-deficient cells by supporting aerobic glycolysis.
Human plasma-like medium facilitates metabolic tracing and enables upregulation of immune signaling pathways in glioblastoma explants.
STUB1-mediated ubiquitination regulates the stability of GLUD1 in lung adenocarcinoma.
Glutamine supplementation reverses manganese neurotoxicity by eliciting the mitochondrial unfolded protein response.
Transcriptional metabolic reprogramming implements meiotic fate decision in mouse testicular germ cells.
Isotopomer analyses with the tricarboxylic acid cycle intermediates and exchanging metabolites from the rat kidney.
Metabolic reprogramming and epigenetic modifications in cancer: from the impacts and mechanisms to the treatment potential.
Lipopolysaccharide Promotes Apoptosis and Oxidative Injury of Porcine Small Intestinal Epithelial Cells by Down-Regulating the Expression of Glutamine Transporter ASCT2.

BMB Rep. 2023 Jul 04. pii: 5877. [Epub ahead of print]

Regulation of glucose and glutamine metabolism to overcome cisplatin resistance in intrahepatic cholangiocarcinoma.

So Mi Yang, Jueun Kim, Ji-Yeon Lee, Jung-Shin Lee, Ji Min Lee.

Intrahepatic cholangiocarcinoma (ICC) is one of the bile duct cancers and a rare malignant tumor with a poor prognosis owing to a lack of early diagnosis and resistance to conventional chemotherapy. A combination of gemcitabine and cisplatin is a treatment approach typically being attempted for the first line. However, its underlying mechanism of resistance to chemotherapy is poorly understood. We addressed this by studying the dynamics in the human ICC SCK cell line. Here, we report that the regulation of glucose and glutamine metabolism is a key factor in overcoming cisplatin resistance of SCK. Through RNA sequencing analysis, we discovered that the cell cycle-related gene set exhibits a high enrichment score in cisplatin-resistant SCK (SCK-R) cells rather than parental SCK (SCK WT) cells. Cell cycle progression correlates with increased nutrient requirement and cancer proliferation or metastasis. Commonly, cancer cells are dependent upon glucose and glutamine availability for survival and proliferation. Indeed, we observed increased expression of GLUT (glucose transporter), ASCT2 (glutamine transporter), and cancer progression markers in SCK-R cells. Thus, we inhibited enhanced metabolic reprogramming in SCK-R cells through nutrient starvation. Especially under glucose starvation, SCK-R cells are sensitized to cisplatin. Moreover, glutaminase-1 (GLS1), which is a mitochondrial enzyme involved in tumorigenesis and progression in cancer cells was upregulated in SCK-R cells. Targeting GLS1 with the GLS1 inhibitor CB-839 (telaglenastat) effectively reduced the expression of cancer progression markers. Taken together, our study suggests that a combination of GLUT inhibition, which mimics glucose starvation, and GLS1 inhibition could be a therapeutic strategy to increase the chemosensitivity of ICC.
J Nanobiotechnology. 2023 Jul 08. 21(1): 214

CAFs targeted ultrasound-responsive nanodroplets loaded V9302 and GLULsiRNA to inhibit melanoma growth via glutamine metabolic reprogramming and tumor microenvironment remodeling.

Chen Ai, Xiao Sun, Shan Xiao, Lu Guo, Mengmeng Shang, Dandan Shi, Dong Meng, Yading Zhao, Xiaoxuan Wang, Jie Li.

  Despite rapid advances in metabolic therapies over the past decade, their efficacy in melanoma has been modest, largely due to the interaction between cancer-associated fibroblasts (CAFs) and cancer cells to promote cancer growth. Altering the tumor microenvironment (TME) is challenging and elusive. CAFs is critical for glutamine deprivation survival in melanoma. In this research, we assembled a CAFs-targeted, controlled-release nanodroplets for the combined delivery of the amino acid transporter ASCT2 (SLC1A5) inhibitor V9302 and GLULsiRNA (siGLUL). The application of ultrasound-targeted microbubble disruption (UTMD) allows for rapid release of V9302 and siGLUL, jointly breaking the glutamine metabolism interaction between CAFs and cancer cells on one hand, on the other hand, blocking activated CAFs and reducing the expression of extracellular matrix (ECM) to facilitate drug penetration. In addition, ultrasound stimulation made siGLUL more accessible to tumor cells and CAFs, downregulating GLUL expression in both cell types. FH-V9302-siGLUL-NDs also serve as contrast-enhanced ultrasound imaging agents for tumor imaging. Our study developed and reported FH-NDs as nanocarriers for V9302 and siGLUL, demonstrating that FH-V9302-siGLUL-NDs have potential bright future applications for integrated diagnostic therapy. Graphical Abstract.

Keywords:  Cancer-associated fibroblasts (CAFs); Glutamine metabolism; Metabolic reprogramming; Tumor microenvironment (TME); Ultrasound

DOI:  https://doi.org/10.1186/s12951-023-01979-z
Nature. 2023 Jul 05.

SLC38A2 and glutamine signalling in cDC1s dictate anti-tumour immunity.

Chuansheng Guo, Zhiyuan You, Hao Shi, Yu Sun, Xingrong Du, Gustavo Palacios, Cliff Guy, Sujing Yuan, Nicole M Chapman, Seon Ah Lim, Xiang Sun, Jordy Saravia, Sherri Rankin, Yogesh Dhungana, Hongbo Chi.

Cancer cells evade T cell-mediated killing through tumour-immune interactions whose mechanisms are not well understood1,2. Dendritic cells (DCs), especially type-1 conventional DCs (cDC1s), mediate T cell priming and therapeutic efficacy against tumours3. DC functions are orchestrated by pattern recognition receptors3-5, although other signals involved remain incompletely defined. Nutrients are emerging mediators of adaptive immunity6-8, but whether nutrients affect DC function or communication between innate and adaptive immune cells is largely unresolved. Here we establish glutamine as an intercellular metabolic checkpoint that dictates tumour-cDC1 crosstalk and licenses cDC1 function in activating cytotoxic T cells. Intratumoral glutamine supplementation inhibits tumour growth by augmenting cDC1-mediated CD8+ T cell immunity, and overcomes therapeutic resistance to checkpoint blockade and T cell-mediated immunotherapies. Mechanistically, tumour cells and cDC1s compete for glutamine uptake via the transporter SLC38A2 to tune anti-tumour immunity. Nutrient screening and integrative analyses show that glutamine is the dominant amino acid in promoting cDC1 function. Further, glutamine signalling via FLCN impinges on TFEB function. Loss of FLCN in DCs selectively impairs cDC1 function in vivo in a TFEB-dependent manner and phenocopies SLC38A2 deficiency by eliminating the anti-tumour therapeutic effect of glutamine supplementation. Our findings establish glutamine-mediated intercellular metabolic crosstalk between tumour cells and cDC1s that underpins tumour immune evasion, and reveal glutamine acquisition and signalling in cDC1s as limiting events for DC activation and putative targets for cancer treatment.

DOI: https://doi.org/10.1038/s41586-023-06299-8
Nutr Cancer. 2023 Jul 04. 1-12

LncRNA PVT1 Confers Cisplatin Resistance of Esophageal Cancer Cells through Modulating the miR-181a-5p-Glutaminase (GLS) Axis.

Zhe Chen, Qinning Wang, Lujie Huang, Guodong Xu, Jing Hu.

Esophageal carcinoma (ESCA) is one of the prevalent malignancies worldwide. Cisplatin (CDDP) is a conventional chemotherapy drug. However, the acquired cisplatin resistance limits its extensively clinical applications. In this study, the roles and underlying mechanisms of lncRNA PVT1 in cisplatin-resistant ESCA are investigated. PVT1 was significantly upregulated in ESCA patient specimens and cell lines. Higher PVT1 level was associated with a poor survival rate of ESCA patients. Silencing PVT1 effectively increased cisplatin sensitivity of ESCA cells. We established cisplatin-resistant ESCA cell line (EC109 CDDP Res) and detected that PVT1 and glutamine metabolism were remarkedly elevated in CDDP-resistant esophageal cancer cells. Bioinformatical analysis and luciferase assay illustrated that PVT1 sponged miR-181a-5p to form a ceRNA network, resulting in the downregulation of miR-181a-5p expression in ESCA cells. Glutaminase (GLS), which is a key enzyme in the glutamine metabolism, was identified and validated as a direct target of miR-181-5p in ESCA cells. Inhibiting glutamine metabolism effectively re-sensitized CDDP-resistant cells. Rescue experiments demonstrated that restoration of miR-181a-5p in PVT1-overexpressing CDDP-resistant ESCA cells successfully overcame the PVT1-promoted cisplatin resistance through targeting GLS. Summarily, our study revealed molecular mechanisms of the lncRNA PVT1-promoted cisplatin resistance in ESCA by modulating the miR-181a-5p-GLS axis.

DOI: https://doi.org/10.1080/01635581.2023.2166540
PLoS One. 2023 ;18(7): e0286525

Tissue-specific reprogramming of glutamine metabolism maintains tolerance to sepsis.

Brooks P Leitner, Won D Lee, Wanling Zhu, Xinyi Zhang, Rafael C Gaspar, Zongyu Li, Joshua D Rabinowitz, Rachel J Perry.

Reprogramming metabolism is of great therapeutic interest for reducing morbidity and mortality during sepsis-induced critical illness. Disappointing results from randomized controlled trials targeting glutamine and antioxidant metabolism in patients with sepsis have begged a deeper understanding of the tissue-specific metabolic response to sepsis. The current study sought to fill this gap. We analyzed skeletal muscle transcriptomics of critically ill patients, versus elective surgical controls, which revealed reduced expression of genes involved in mitochondrial metabolism and electron transport, with increases in glutathione cycling, glutamine, branched chain, and aromatic amino acid transport. We then performed untargeted metabolomics and 13C isotope tracing to analyze systemic and tissue specific metabolic phenotyping in a murine polymicrobial sepsis model. We found an increased number of correlations between the metabolomes of liver, kidney, and spleen, with loss of correlations between the heart and quadriceps and all other organs, pointing to a shared metabolic signature within vital abdominal organs, and unique metabolic signatures for muscles during sepsis. A lowered GSH:GSSG and elevated AMP:ATP ratio in the liver underlie the significant upregulation of isotopically labeled glutamine's contribution to TCA cycle anaplerosis and glutamine-derived glutathione biosynthesis; meanwhile, the skeletal muscle and spleen were the only organs where glutamine's contribution to the TCA cycle was significantly suppressed. These results highlight tissue-specific mitochondrial reprogramming to support liver energetic demands and antioxidant synthesis, rather than global mitochondrial dysfunction, as a metabolic consequence of sepsis.

DOI: https://doi.org/10.1371/journal.pone.0286525
Cell Rep. 2023 Jul 04. pii: S2211-1247(23)00756-8. [Epub ahead of print]42(7): 112745

Targeting CXCR1 alleviates hyperoxia-induced lung injury through promoting glutamine metabolism.

Hao Qin, Wei Zhuang, Xiucheng Liu, Junqi Wu, Shenghui Li, Yang Wang, Xiangming Liu, Chang Chen, Hao Zhang.

  Although increasing evidence suggests potential iatrogenic injury from supplemental oxygen therapy, significant exposure to hyperoxia in critically ill patients is inevitable. This study shows that hyperoxia causes lung injury in a time- and dose-dependent manner. In addition, prolonged inspiration of oxygen at concentrations higher than 80% is found to cause redox imbalance and impair alveolar microvascular structure. Knockout of C-X-C motif chemokine receptor 1 (Cxcr1) inhibits the release of reactive oxygen species (ROS) from neutrophils and synergistically enhances the ability of endothelial cells to eliminate ROS. We also combine transcriptome, proteome, and metabolome analysis and find that CXCR1 knockdown promotes glutamine metabolism and leads to reduced glutathione by upregulating the expression of malic enzyme 1. This preclinical evidence suggests that a conservative oxygen strategy should be recommended and indicates that targeting CXCR1 has the potential to restore redox homeostasis by reducing oxygen toxicity when inspiratory hyperoxia treatment is necessary.

Keywords:  C-X-C motif chemokine receptor 1; CP: Metabolism; acute lung injury; glutamine metabolism; hyperoxia; redox homeostasis

DOI:  https://doi.org/10.1016/j.celrep.2023.112745
Cell Death Dis. 2023 Jul 06. 14(7): 403

Pyruvate transamination and NAD biosynthesis enable proliferation of succinate dehydrogenase-deficient cells by supporting aerobic glycolysis.

Luisa Ricci, Federico Uchenna Stanley, Tanja Eberhart, Francesco Mainini, David Sumpton, Simone Cardaci.

Succinate dehydrogenase (SDH) is the mitochondrial enzyme converting succinate to fumarate in the tricarboxylic acid (TCA) cycle. SDH acts as a tumor suppressor with germline loss-of-function mutations in its encoding genes predisposing to aggressive familial neuroendocrine and renal cancer syndromes. Lack of SDH activity disrupts the TCA cycle, imposes Warburg-like bioenergetic features, and commits cells to rely on pyruvate carboxylation for anabolic needs. However, the spectrum of metabolic adaptations enabling SDH-deficient tumors to cope with a dysfunctional TCA cycle remains largely unresolved. By using previously characterized Sdhb-deleted kidney mouse cells, here we found that SDH deficiency commits cells to rely on mitochondrial glutamate-pyruvate transaminase (GPT2) activity for proliferation. We showed that GPT2-dependent alanine biosynthesis is crucial to sustain reductive carboxylation of glutamine, thereby circumventing the TCA cycle truncation determined by SDH loss. By driving the reductive TCA cycle anaplerosis, GPT2 activity fuels a metabolic circuit maintaining a favorable intracellular NAD+ pool to enable glycolysis, thus meeting the energetic demands of SDH-deficient cells. As a metabolic syllogism, SDH deficiency confers sensitivity to NAD+ depletion achieved by pharmacological inhibition of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD+ salvage pathway. Beyond identifying an epistatic functional relationship between two metabolic genes in the control of SDH-deficient cell fitness, this study disclosed a metabolic strategy to increase the sensitivity of tumors to interventions limiting NAD availability.

DOI: https://doi.org/10.1038/s41419-023-05927-5
bioRxiv. 2023 May 31. pii: 2023.05.29.542774. [Epub ahead of print]

Human plasma-like medium facilitates metabolic tracing and enables upregulation of immune signaling pathways in glioblastoma explants.

Mohamad El Shami, Milan R Savani, Lauren C Gattie, Bailey Smith, William H Hicks, Jeremy N Rich, Timothy E Richardson, Samuel K McBrayer, Kalil G Abdullah.

Purpose: Metabolism within the tumor microenvironment (TME) represents an increasing area of interest to understand glioma initiation and progression. Stable isotope tracing is a technique critical to the study of tumor metabolism. Cell culture models of this disease are not routinely cultured under physiologically relevant nutrient conditions and do not retain cellular heterogeneity present in the parental TME. Moreover, in vivo, stable isotope tracing in intracranial glioma xenografts, the gold standard for metabolic investigation, is time consuming and technically challenging. To provide insights into glioma metabolism in the presence of an intact TME, we performed stable isotope tracing analysis of patient-derived, heterocellular Surgically eXplanted Organoid (SXO) glioma models in human plasma-like medium (HPLM).Methods: Glioma SXOs were established and cultured in conventional media or transitioned to HPLM. We evaluated SXO cytoarchitecture and histology, then performed spatial transcriptomic profiling to identify cellular populations and differential gene expression patterns. We performed stable isotope tracing with 15 N 2 -glutamine to evaluate intracellular metabolite labeling patterns.
Results: Glioma SXOs cultured in HPLM retain cytoarchitecture and cellular constituents. Immune cells in HPLM-cultured SXOs demonstrated increased transcription of immune-related signatures, including innate immune, adaptive immune, and cytokine signaling programs. 15 N isotope enrichment from glutamine was observed in metabolites from diverse pathways, and labeling patterns were stable over time.
Conclusion: To enable ex vivo, tractable investigations of whole tumor metabolism, we developed an approach to conduct stable isotope tracing in glioma SXOs cultured under physiologically relevant nutrient conditions. Under these conditions, SXOs maintained viability, composition, and metabolic activity while exhibiting increased immune-related transcriptional programs.

DOI: https://doi.org/10.1101/2023.05.29.542774
iScience. 2023 Jul 21. 26(7): 107151

STUB1-mediated ubiquitination regulates the stability of GLUD1 in lung adenocarcinoma.

Qifan Hu, Jiapeng Lei, Zhujun Cheng, Jing Xu, Lei Wang, Yi Yuan, Mingxi Gan, Yanan Wang, Yilin Xie, Lu Yao, Keru Wang, Yuhan Liu, Wenze Xun, Jian-Bin Wang, Tianyu Han.

  The dysregulation of glutamine metabolism provides survival advantages for tumors by supplementing tricarboxylic acid cycle. Glutamate dehydrogenase 1 (GLUD1) is one of the key enzymes in glutamine catabolism. Here, we found that enhanced protein stability was the key factor for the upregulation of GLUD1 in lung adenocarcinoma. We discovered that GLUD1 showed a high protein expression in lung adenocarcinoma cells or tissues. We elucidated that STIP1 homology and U-box-containing protein 1 (STUB1) was the key E3 ligase responsible for ubiquitin-mediated proteasomal degradation of GLUD1. We further showed that lysine 503 (K503) was the main ubiquitination site of GLUD1, inhibiting the ubiquitination at this site promoted the proliferation and tumor growth of lung adenocarcinoma cells. Taken together, this study clarifies the molecular mechanism of GLUD1 in maintaining protein homeostasis in lung adenocarcinoma, which provides a theoretical basis for the development of anti-cancer drugs targeting GLUD1.

Keywords:  Biological sciences; Cancer; Cell biology; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2023.107151
iScience. 2023 Jul 21. 26(7): 107136

Glutamine supplementation reverses manganese neurotoxicity by eliciting the mitochondrial unfolded protein response.

Shixuan Zhang, Junrou Zhang, Luli Wu, Li Chen, Piye Niu, Jie Li.

  Excessive exposure to manganese (Mn) can cause neurological abnormalities, but the mechanism of Mn neurotoxicity remains unclear. Previous studies have shown that abnormal mitochondrial metabolism is a crucial mechanism underlying Mn neurotoxicity. Therefore, improving neurometabolic in neuronal mitochondria may be a potential therapy for Mn neurotoxicity. Here, single-cell sequencing revealed that Mn affected mitochondrial neurometabolic pathways and unfolded protein response in zebrafish dopaminergic neurons. Metabolomic analysis indicated that Mn inhibited the glutathione metabolic pathway in human neuroblastoma (SH-SY5Y) cells. Mechanistically, Mn exposure inhibited glutathione (GSH) and mitochondrial unfolded protein response (UPRmt). Furthermore, supplementation with glutamine (Gln) can effectively increase the concentration of GSH and triggered UPRmt which can alleviate mitochondrial dysfunction and counteract the neurotoxicity of Mn. Our findings highlight that UPRmt is involved in Mn-induced neurotoxicity and glutathione metabolic pathway affects UPRmt to reverse Mn neurotoxicity. In addition, Gln supplementation may have potential therapeutic benefits for Mn-related neurological disorders.

Keywords:  Biochemistry; Cell biology; Metabolomics; Toxicology; Transcriptomics

DOI:  https://doi.org/10.1016/j.isci.2023.107136
Cell Rep. 2023 Jul 04. pii: S2211-1247(23)00760-X. [Epub ahead of print]42(7): 112749

Transcriptional metabolic reprogramming implements meiotic fate decision in mouse testicular germ cells.

Xiaoyu Zhang, Yan Liu, Froylan Sosa, Sumedha Gunewardena, Peter A Crawford, Amanda C Zielen, Kyle E Orwig, Ning Wang.

  Nutrient starvation drives yeast meiosis, whereas retinoic acid (RA) is required for mammalian meiosis through its germline target Stra8. Here, by using single-cell transcriptomic analysis of wild-type and Stra8-deficient juvenile mouse germ cells, our data show that the expression of nutrient transporter genes, including Slc7a5, Slc38a2, and Slc2a1, is downregulated in germ cells during meiotic initiation, and this process requires Stra8, which binds to these genes and induces their H3K27 deacetylation. Consequently, Stra8-deficient germ cells sustain glutamine and glucose uptake in response to RA and exhibit hyperactive mTORC1/protein kinase A (PKA) activities. Importantly, expression of Slc38a2, a glutamine importer, is negatively correlated with meiotic genes in the GTEx dataset, and Slc38a2 knockdown downregulates mTORC1/PKA activities and induces meiotic gene expression. Thus, our study indicates that RA via Stra8, a chordate morphogen pathway, induces meiosis partially by generating a conserved nutrient restriction signal in mammalian germ cells by downregulating their nutrient transporter expression.

Keywords:  CP: Developmental biology; CP: Molecular biology; germline stem cell, meiosis, meiotic initiation, retinoic acid, Stra8, Slc38a2, spermatogonial stem cell, spermatogenesis, germ cell, nutrient

DOI:  https://doi.org/10.1016/j.celrep.2023.112749
NMR Biomed. 2023 Jul 01. e4994

Isotopomer analyses with the tricarboxylic acid cycle intermediates and exchanging metabolites from the rat kidney.

Eunsook S Jin, Xiaodong Wen, Craig R Malloy.

  Renal metabolism is essential for kidney functions and energy homeostasis in the body. The TCA cycle is the hub of metabolism, but the metabolic activities of the cycle in the kidney have rarely been investigated. This study is to assess metabolic processes at the level of the TCA cycle in the kidney based on isotopomer distributions in multiple metabolites. Isolated rat kidneys were perfused with media containing common substrates including lactate and alanine for an hour. One group of kidneys received [U-13 C3 ]lactate instead of natural abundance lactate while the other group received [U-13 C3 ]alanine instead of natural abundance alanine. Perfused kidneys and effluent were prepared for analysis using NMR spectroscopy. 13 C-labeling patterns in glutamate, fumarate, aspartate and succinate from the kidney extracts showed that pyruvate carboxylase and oxidative metabolism through the TCA cycle were comparably very active, but pyruvate cycling and pyruvate dehydrogenase were relatively less active. Isotopomer analyses with fumarate and malate from effluent, however, indicated that pyruvate carboxylase was much more active than the TCA cycle and other metabolic processes. The reverse equilibrium of oxaloacetate with four-carbon intermediates of the cycle was nearly complete (92%), based on the ratio of [2,3,4-13 C3 ]/[1,2,3-13 C3 ] in aspartate or malate. 13 C enrichment in glucose with 13 C-lactate supply was higher than that with 13 C-alanine. Isotopomer analyses with multiple metabolites (i.e., glutamate, fumarate, aspartate, succinate and malate) allowed us to assess relative metabolic processes in the TCA cycle in the kidney supplied with [U-13 C3 ]lactate. Data from the analytes were generally consistent, indicating highly active pyruvate carboxylase and oxidative metabolism through the TCA cycle. Different 13 C-labeling patterns in analytes from the kidney extracts versus effluent suggested metabolic compartmentalization.

Keywords:  NMR; TCA cycle; alanine; fumarate; glutamate; isotopomer; lactate; renal metabolism

DOI:  https://doi.org/10.1002/nbm.4994
Exp Mol Med. 2023 Jul 03.

Metabolic reprogramming and epigenetic modifications in cancer: from the impacts and mechanisms to the treatment potential.

Xuemeng Xu, Qiu Peng, Xianjie Jiang, Shiming Tan, Yiqing Yang, Wenjuan Yang, Yaqian Han, Yuyu Chen, Linda Oyang, Jinguan Lin, Longzheng Xia, Mingjing Peng, Nayiyuan Wu, Yanyan Tang, Jinyun Li, Qianjin Liao, Yujuan Zhou.

Metabolic reprogramming and epigenetic modifications are hallmarks of cancer cells. In cancer cells, metabolic pathway activity varies during tumorigenesis and cancer progression, indicating regulated metabolic plasticity. Metabolic changes are often closely related to epigenetic changes, such as alterations in the expression or activity of epigenetically modified enzymes, which may exert a direct or an indirect influence on cellular metabolism. Therefore, exploring the mechanisms underlying epigenetic modifications regulating the reprogramming of tumor cell metabolism is important for further understanding tumor pathogenesis. Here, we mainly focus on the latest studies on epigenetic modifications related to cancer cell metabolism regulations, including changes in glucose, lipid and amino acid metabolism in the cancer context, and then emphasize the mechanisms related to tumor cell epigenetic modifications. Specifically, we discuss the role played by DNA methylation, chromatin remodeling, noncoding RNAs and histone lactylation in tumor growth and progression. Finally, we summarize the prospects of potential cancer therapeutic strategies based on metabolic reprogramming and epigenetic changes in tumor cells.

DOI: https://doi.org/10.1038/s12276-023-01020-1
J Anim Sci. 2023 Jul 06. pii: skad229. [Epub ahead of print]

Lipopolysaccharide Promotes Apoptosis and Oxidative Injury of Porcine Small Intestinal Epithelial Cells by Down-Regulating the Expression of Glutamine Transporter ASCT2.

Xiaopeng Tang, Kangning Xiong, Jia Liu, Meijun Li.

  The present study aimed to investigate the effects of lipopolysaccharide (LPS) stimulation on oxidative damage, apoptosis, and glutamine (Gln) transporter Alanine-Serine-Cysteine transporter 2 (ASCT2) expression in porcine small intestinal epithelial cells (IPEC-J2), and preliminarily elucidated the relationship between ASCT2 expression level and oxidative damage and apoptosis of IPEC-J2 cells. IPEC-J2 cells were treated without (control group, CON, n=6) or with 1 μg/mL LPS (LPS group, LPS, n=6). Cell viability, lactate dehydrogenase (LDH) content, malonaldehyde (MDA), antioxidant enzymes [superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and total antioxidant capacity (T-AOC)], apoptosis of IPEC-J2 cells, the expression of Caspase3, the expression of ASCT2 mRNA and ASCT2 protein was detected. The results showed that LPS stimulation of IPEC-J2 cells significantly reduced the cell viability, and antioxidant enzymes activity (SOD, CAT and GSH-Px), and significantly increased LDH and MDA release. Flow cytometry results showed that LPS stimulation significantly increased the late apoptosis rate and the total apoptosis rate of IPEC-J2 cells. The immunofluorescence results showed that the fluorescence intensity of LPS stimulated IPEC-J2 cells was significantly enhanced. LPS stimulation significantly decreased the mRNA and protein expression of ASCT2 in IPEC-J2 cells. The correlation analysis showed that ASCT2 expression was negatively correlated with apoptosis, and positively correlated with the antioxidant capacity of IPEC-J2 cells. According to the results of this study, it can be preliminarily concluded that LPS promotes the apoptosis and oxidative injury of IPEC-J2 cells by down-regulating the expression of ASCT2.

Keywords:  ASCT2; apoptosis; cell injury; lipopolysaccharide; porcine small intestinal epithelial cells

DOI:  https://doi.org/10.1093/jas/skad229