bims-glucam 2024-05-05 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2024‒05‒05
eighteen papers selected by
Sreeparna Banerjee, Middle East Technical University

Glutamine metabolism, a double agent combating or fuelling hepatocellular carcinoma.
Tanshinone IIA alleviates pulmonary fibrosis by modulating glutamine metabolic reprogramming based on [U-13C5]-glutamine metabolic flux analysis.
Metabolic reprogramming of tumor-associated macrophages using glutamine antagonist JHU083 drives tumor immunity in myeloid-rich prostate and bladder cancer tumors.
Inhibition of asparagine synthetase effectively retards polycystic kidney disease progression.
Metabolic signature and response to glutamine deprivation are independent of p53 status in B cell malignancies.
METTL3-mediated m6A methylation of SLC38A1 stimulates cervical cancer growth.
Dual targeting of glutamine and serine metabolism in acute myeloid leukemia.
Glutamine-mediated epigenetic regulation of cFLIP underlies resistance to TRAIL in pancreatic cancer.
Regulation of Hypoxia Dependent Reprogramming of Cancer Metabolism: Role of HIF-1 and Its Potential Therapeutic Implications in Leukemia.
Mitochondria and Cancer.
Glutamine-derived aspartate is required for eIF5A hypusination-mediated translation of HIF-1α to induce the polarization of tumor-associated macrophages.
Screening of amino acids as a safe energy source for isolated rat pancreatic acini.
L-type Amino Acid Transporter 1 as a Therapeutic Target in Pancreatic Cancer.
Abnormal changes in metabolites caused by m6A methylation modification: The leading factors that induce the formation of immunosuppressive tumor microenvironment and their promising potential for clinical application.
Targeting metabolism of breast cancer and its implications in T cell immunotherapy.
Dietary intake and glutamine-serine metabolism control pathologic vascular stiffness.
Investigation of the effects of thiazole compounds on thioredoxin reductase 1 (TrxR1), glutathione S-transferase (GST), and glutathione reductase (GR) targeted human brain glioblastoma cancer (U-87 MG).
HCMMD: systematic evaluation of metabolites in body fluids as liquid biopsy biomarker for human cancers.

JHEP Rep. 2024 May;6(5): 101077

Glutamine metabolism, a double agent combating or fuelling hepatocellular carcinoma.

Razan Abou Ziki, Sabine Colnot.

  The reprogramming of glutamine metabolism is a key event in cancer more generally and in hepatocellular carcinoma (HCC) in particular. Glutamine consumption supplies tumours with ATP and metabolites through anaplerosis of the tricarboxylic acid cycle, while glutamine production can be enhanced by the overexpression of glutamine synthetase. In HCC, increased glutamine production is driven by activating mutations in the CTNNB1 gene encoding β-catenin. Increased glutamine synthesis or utilisation impacts tumour epigenetics, oxidative stress, autophagy, immunity and associated pathways, such as the mTOR (mammalian target of rapamycin) pathway. In this review, we will discuss studies which emphasise the pro-tumoral or tumour-suppressive effect of glutamine overproduction. It is clear that more comprehensive studies are needed as a foundation from which to develop suitable therapies targeting glutamine metabolic pathways, depending on the predicted pro- or anti-tumour role of dysregulated glutamine metabolism in distinct genetic contexts.

Keywords:  Hepatocellular carcinoma; beta-catenin; glutaminase; glutamine metabolism; glutamine synthetase; liver zonation

DOI:  https://doi.org/10.1016/j.jhepr.2024.101077
J Adv Res. 2024 Apr 30. pii: S2090-1232(24)00172-3. [Epub ahead of print]

Tanshinone IIA alleviates pulmonary fibrosis by modulating glutamine metabolic reprogramming based on [U-13C5]-glutamine metabolic flux analysis.

Baixi Shan, Congying Guo, Haoyan Zhou, Jun Chen.

  INTRODUCTION: Glutamine metabolic reprogramming, mediated by glutaminase (GLS), is an important signal during pulmonary fibrosis (PF) progression. Tanshinone IIA (Tan IIA) is a naturally lipophilic diterpene with antioxidant and antifibrotic properties. However, the potential mechanisms of Tan IIA for regulating glutamine metabolic reprogramming are not yet clear.OBJECTIVES: This study aimed was to evaluate the role of Tan IIA in intervening in glutamine metabolic reprogramming to exert anti-PF and to explore the potential new mechanisms of metabolic regulation.
METHODS: Fibrotic characteristics was detected via immunofluorescence and western blotting analysis. Cell proliferation was examined with EdU Assay. Cell metabolites were labeled by using stable isotope [U-13C5]-glutamine. By utilizing 100% 13C glutamine tracers and employing network analysis to investigate the activation of metabolic pathways in fibroblasts, as well as evaluating the impact of Tan IIA on these pathways, we accurately quantified the absolute flux of glutaminolysis, proline synthesis, and the TCA cycle pathway using isotopomer network compartmental analysis (INCA), a user-friendly software tool for 13C metabolic flux analysis (13C-MFA). Molecular docking was used for identifying the binding of Tan IIA with target protein.
RESULTS: Tan IIA ameliorate TGF-β1-induced myofibroblast proliferation, reduce collagen I and III and α-SMA protein expression in MRC-5 and NIH-3 T3 cells. Furthermore, Tan IIA regulate mitochondrial energy metabolism by modulating TGF-β1-stimulated glutamine metabolic reprogramming in NIH-3 T3 cells and inhibiting GLS1 expression, which reduced the metabolic flux of glutamine into mitochondria in myofibroblasts, and also targeted inhibited the expression of Δ1-pyrroline-5-carboxylate synthase (P5CS), P5C reductase 1 (PYCR1), and phosphoserine aminotransferase 1 (PSAT1), and reduced proline hydroxylation and blocked the collagen synthesis pathway.
CONCLUSION: Tan IIA reverses glutamine metabolic reprogramming, reduces mitochondrial energy expenditure, and inhibits collagen matrix synthesis by modulating potential targets in glutamine metabolism. This novel perspective sheds light on the essential role of glutamine metabolic reprogramming in PF.

Keywords:  (13)C metabolic flux analysis; Cellular energy metabolism; Glutamine metabolic reprogramming; Pulmonary fibrosis; Tanshinone IIA; [U-(13)C(5)]-glutamine

DOI:  https://doi.org/10.1016/j.jare.2024.04.029
Cancer Immunol Res. 2024 May 03.

Metabolic reprogramming of tumor-associated macrophages using glutamine antagonist JHU083 drives tumor immunity in myeloid-rich prostate and bladder cancer tumors.

Monali Praharaj, Fan Shen, Alex J Lee, Liang Zhao, Thomas R Nirschl, Debebe Theodros, Alok K Singh, Xiaoxu Wang, Kenneth M Adusei, Kara A Lombardo, Raekwon A Williams, Laura A Sena, Elizabeth A Thompson, Ada Tam, Srinivasan Yegnasubramanian, Edward J Pearce, Robert D Leone, Jesse Alt, Rana Rais, Barbara S Slusher, Drew M Pardoll, Jonathan D Powell, Jelani C Zarif.

Glutamine metabolism in tumor microenvironments critically regulates anti-tumor immunity. Using glutamine-antagonist prodrug JHU083, we report potent tumor growth inhibition in urologic tumors by JHU083-reprogrammed tumor-associated macrophages (TAMs) and tumor-infiltrating monocytes (TIMs). We show JHU083-mediated glutamine antagonism in tumor microenvironments induces TNF, pro-inflammatory, and mTORC1 signaling in intratumoral TAM clusters. JHU083-reprogrammed TAMs also exhibit increased tumor cell phagocytosis and diminished pro-angiogenic capacities. In vivo inhibition of TAM glutamine consumption resulted in increased glycolysis, a broken TCA cycle, and purine metabolism disruption. Although the anti-tumor effect of glutamine antagonism on tumor-infiltrating T cells was moderate, JHU083 promoted a stem cell-like phenotype in CD8+ T cells and decreased Treg abundance. Finally, JHU083 caused a ubiquitous shutdown in glutamine utilizing metabolic pathways in tumor cells, leading to reduced HIF-1alpha, c-MYC phosphorylation, and induction of tumor cell apoptosis, all key anti-tumor features.

DOI: https://doi.org/10.1158/2326-6066.CIR-23-1105
EMBO Mol Med. 2024 Apr 29.

Inhibition of asparagine synthetase effectively retards polycystic kidney disease progression.

Sara Clerici, Christine Podrini, Davide Stefanoni, Gianfranco Distefano, Laura Cassina, Maria Elena Steidl, Laura Tronci, Tamara Canu, Marco Chiaravalli, Daniel Spies, Thomas A Bell, Ana Sh Costa, Antonio Esposito, Angelo D'Alessandro, Christian Frezza, Angela Bachi, Alessandra Boletta.

  Polycystic kidney disease (PKD) is a genetic disorder characterized by bilateral cyst formation. We showed that PKD cells and kidneys display metabolic alterations, including the Warburg effect and glutaminolysis, sustained in vitro by the enzyme asparagine synthetase (ASNS). Here, we used antisense oligonucleotides (ASO) against Asns in orthologous and slowly progressive PKD murine models and show that treatment leads to a drastic reduction of total kidney volume (measured by MRI) and a prominent rescue of renal function in the mouse. Mechanistically, the upregulation of an ATF4-ASNS axis in PKD is driven by the amino acid response (AAR) branch of the integrated stress response (ISR). Metabolic profiling of PKD or control kidneys treated with Asns-ASO or Scr-ASO revealed major changes in the mutants, several of which are rescued by Asns silencing in vivo. Indeed, ASNS drives glutamine-dependent de novo pyrimidine synthesis and proliferation in cystic epithelia. Notably, while several metabolic pathways were completely corrected by Asns-ASO, glycolysis was only partially restored. Accordingly, combining the glycolytic inhibitor 2DG with Asns-ASO further improved efficacy. Our studies identify a new therapeutic target and novel metabolic vulnerabilities in PKD.

Keywords:  ADPKD; Antisense Oligonucleotides; Glutamine Metabolism; Glycolysis; Metabolic Reprogramming

DOI:  https://doi.org/10.1038/s44321-024-00071-9
iScience. 2024 May 17. 27(5): 109640

Metabolic signature and response to glutamine deprivation are independent of p53 status in B cell malignancies.

Chiara Montironi, Zhenghao Chen, Ingrid A M Derks, Gaspard Cretenet, Esmée A Krap, Eric Eldering, Helga Simon-Molas.

  The tumor suppressor p53 has been described to control various aspects of metabolic reprogramming in solid tumors, but in B cell malignancies that role is as yet unknown. We generated pairs of p53 functional and knockout (KO) clones from distinct B cell malignancies (acute lymphoblastic leukemia, chronic lymphocytic leukemia, diffuse large B cell lymphoma, and multiple myeloma). Metabolomics and isotope tracing showed that p53 loss did not drive a common metabolic signature. Instead, cell lines segregated according to cell of origin. Next, we focused on glutamine as a crucial energy source in the B cell tumor microenvironment. In both TP53 wild-type and KO cells, glutamine deprivation induced cell death through the integrated stress response, via CHOP/ATF4. Lastly, combining BH3 mimetic drugs with glutamine starvation emerged as a possibility to target resistant clones. In conclusion, our analyses do not support a common metabolic signature of p53 deficiency in B cell malignancies and suggest therapeutic options for exploration based on glutamine dependency.

Keywords:  Cancer; Cell biology; Metabolomics; Microenvironment

DOI:  https://doi.org/10.1016/j.isci.2024.109640
Biochem Biophys Res Commun. 2024 Apr 30. pii: S0006-291X(24)00575-8. [Epub ahead of print]716 150039

METTL3-mediated m6A methylation of SLC38A1 stimulates cervical cancer growth.

Hai-Ting Liu, Yun Zhao, Hong-Cai Wang, Qing-Ling Liu.

  The objective of this study was to better characterize the role of the glutamine transporter SLC38A1 in cervical cancer and explore the underlying mechanisms. Data from public databases and clinical cervical cancer tissue samples were used to assess the expression of SLC38A1 and its prognostic significance. Immunohistochemical staining, qRT-PCR, and Western blotting were used to evaluate the expression of relevant genes and proteins. Cell viability, cell cycle, apoptosis, and intracellular glutamine content were measured using CCK-8, flow cytometry, and biochemical assays. Additionally, the RNA immunoprecipitation (RIP) assay was used to examine the impact of METTL3/IGF2BP3 on the m6A modification of the SLC38A1 3'UTR. Both cervical cancer specimens and cells showed significantly increased expression of SLC38A1 and its expression correlated with an unfavorable prognosis. Knockdown of SLC38A1 inhibited cell viability and cell cycle progression, induced apoptosis, and suppressed tumor growth in vivo. Glutaminase-1 inhibitor CB-839 reversed the effects of SLC38A1 overexpression. METTL3 promoted m6A modification of SLC38A1 and enhanced its mRNA stability through IGF2BP3 recruitment. Moreover, METTL3 silencing inhibited cell viability, cell cycle progression, intracellular glutamine content, and induced apoptosis, but these effects were reversed by SLC38A1 overexpression. In conclusion, METTL3-mediated m6A methylation of SLC38A1 stimulates cervical cancer progression. SLC38A1 inhibition is a potential therapeutic strategy for cervical cancer.

Keywords:  Cervical cancer; Glutamine; IGF2BP3; METTL3; SLC38A1; m(6)A RNA methylation

DOI:  https://doi.org/10.1016/j.bbrc.2024.150039
Front Oncol. 2024 ;14 1326754

Dual targeting of glutamine and serine metabolism in acute myeloid leukemia.

Kanwal M Hameed, Dominique R Bollino, Amol C Shetty, Brandon Carter-Cooper, Rena G Lapidus, Ashkan Emadi.

  Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy characterized by disrupted blood cell production and function. Recent investigations have highlighted the potential of targeting glutamine metabolism as a promising therapeutic approach for AML. Asparaginases, enzymes that deplete circulating glutamine and asparagine, are approved for the treatment of acute lymphoblastic leukemia, but are also under investigation in AML, with promising results. We previously reported an elevation in plasma serine levels following treatment with Erwinia-derived asparaginase (also called crisantaspase). This led us to hypothesize that AML cells initiate the de novo serine biosynthesis pathway in response to crisantaspase treatment and that inhibiting this pathway in combination with crisantaspase would enhance AML cell death. Here we report that in AML cell lines, treatment with the clinically available crisantaspase, Rylaze, upregulates the serine biosynthesis enzymes phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase (PSAT1) through activation of the Amino Acid Response (AAR) pathway, a cellular stress response mechanism that regulates amino acid metabolism and protein synthesis under conditions of nutrient limitation. Inhibition of serine biosynthesis through CRISPR-Cas9-mediated knockout of PHGDH resulted in a ~250-fold reduction in the half-maximal inhibitory concentration (IC50) for Rylaze, indicating heightened sensitivity to crisantaspase therapy. Treatment of AML cells with a combination of Rylaze and a small molecule inhibitor of PHGDH (BI4916) revealed synergistic anti-proliferative effects in both cell lines and primary AML patient samples. Rylaze-BI4916 treatment in AML cell lines led to the inhibition of cap-dependent mRNA translation and protein synthesis, as well as a marked decrease in intracellular glutathione levels, a critical cellular antioxidant. Collectively, our results highlight the clinical potential of targeting serine biosynthesis in combination with crisantaspase as a novel therapeutic strategy for AML.

Keywords:  asparaginase; cancer metabolism; glutamine; leukemia; serine

DOI:  https://doi.org/10.3389/fonc.2024.1326754
Exp Mol Med. 2024 Apr;56(4): 1013-1026

Glutamine-mediated epigenetic regulation of cFLIP underlies resistance to TRAIL in pancreatic cancer.

Ji Hye Kim, Jinyoung Lee, Se Seul Im, Boyun Kim, Eun-Young Kim, Hyo-Jin Min, Jinbeom Heo, Eun-Ju Chang, Kyung-Chul Choi, Dong-Myung Shin, Jaekyoung Son.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent because it kills cancer cells while sparing normal cells. However, many cancers, including pancreatic ductal adenocarcinoma (PDAC), exhibit intrinsic or acquired resistance to TRAIL, and the molecular mechanisms underlying TRAIL resistance in cancers, particularly in PDAC, remain unclear. In this study, we demonstrated that glutamine (Gln) endows PDAC cells with resistance to TRAIL through KDM4C-mediated epigenetic regulation of cFLIP. Inhibition of glutaminolysis significantly reduced the cFLIP level, leading to TRAIL-mediated formation of death-inducing signaling complexes. Overexpression of cFLIP dramatically rescued PDAC cells from TRAIL/Gln deprivation-induced apoptosis. Alpha-Ketoglutarate (aKG) supplementation significantly reversed the decrease in the cFLIP level induced by glutaminolysis inhibition and rescued PDAC cells from TRAIL/Gln deprivation-induced apoptosis. Knockdown of glutamic-oxaloacetic transaminase 2, which facilitates the conversion of oxaloacetate and glutamate into aspartate and aKG, decreased aKG production and the cFLIP level and activated TRAIL-induced apoptosis. AKG-mediated epigenetic regulation was necessary for maintaining a high level of cFLIP. Glutaminolysis inhibition increased the abundance of H3K9me3 in the cFLIP promoter, indicating that Gln-derived aKG production is important for Jumonji-domain histone demethylase (JHDM)-mediated cFLIP regulation. The JHDM KDM4C regulated cFLIP expression by binding to its promoter, and KDM4C knockdown sensitized PDAC cells to TRAIL-induced apoptosis. The present findings suggest that Gln-derived aKG production is required for KDM4C-mediated epigenetic regulation of cFLIP, which leads to resistance to TRAIL.

DOI: https://doi.org/10.1038/s12276-024-01231-0
Asian Pac J Cancer Prev. 2024 Apr 01. pii: 91091. [Epub ahead of print]25(4): 1121-1134

Regulation of Hypoxia Dependent Reprogramming of Cancer Metabolism: Role of HIF-1 and Its Potential Therapeutic Implications in Leukemia.

Sandeep Pandey, Ranjana Singh, Nimra Habib, Ramesh Mani Tripathi, Rashmi Kushwaha, Abbas Ali Mahdi.

  Metabolic reprogramming occurs to meet cancer cells' high energy demand. Its function is essential to the survival of malignancies. Comparing cancer cells to non-malignant cells has revealed that cancer cells have altered metabolism. Several pathways, particularly mTOR, Akt, PI3K, and HIF-1 (hypoxia-inducible factor-1) modulate the metabolism of cancer. Among other aspects of cancer biology, gene expression in metabolism, survival, invasion, proliferation, and angiogenesis of cells are controlled by HIF-1, a vital controller of cellular responsiveness to hypoxia. This article examines various cancer cell metabolisms, metabolic alterations that can take place in cancer cells, metabolic pathways, and molecular aspects of metabolic alteration in cancer cells placing special attention on the consequences of hypoxia-inducible factor and summarising some of their novel targets in the treatment of cancer including leukemia. A brief description of HIF-1α's role and target in a few common types of hematological malignancies (leukemia) is also elucidated in the present article.

Keywords:  Cancer Cell Metabolism; Hematological malignancies; Hypoxia-Inducible Factor-1 (HIF-1); Metabolic Reprogramming; cancer therapeutics

DOI:  https://doi.org/10.31557/APJCP.2024.25.4.1121
Cold Spring Harb Perspect Med. 2024 May 01. pii: a041534. [Epub ahead of print]

Mitochondria and Cancer.

Timothy C Kenny, Kıvanç Birsoy.

Mitochondria are semiautonomous organelles with diverse metabolic and cellular functions including anabolism and energy production through oxidative phosphorylation. Following the pioneering observations of Otto Warburg nearly a century ago, an immense body of work has examined the role of mitochondria in cancer pathogenesis and progression. Here, we summarize the current state of the field, which has coalesced around the position that functional mitochondria are required for cancer cell proliferation. In this review, we discuss how mitochondria influence tumorigenesis by impacting anabolism, intracellular signaling, and the tumor microenvironment. Consistent with their critical functions in tumor formation, mitochondria have become an attractive target for cancer therapy. We provide a comprehensive update on the numerous therapeutic modalities targeting the mitochondria of cancer cells making their way through clinical trials.

DOI: https://doi.org/10.1101/cshperspect.a041534
Exp Mol Med. 2024 May 01.

Glutamine-derived aspartate is required for eIF5A hypusination-mediated translation of HIF-1α to induce the polarization of tumor-associated macrophages.

Dong-Ho Kim, Yoo Na Kang, Jonghwa Jin, Mihyang Park, Daehoon Kim, Ghilsuk Yoon, Jae Won Yun, Jaebon Lee, Soo Young Park, Yu Rim Lee, Jun-Kyu Byun, Yeon-Kyung Choi, Keun-Gyu Park.

Tumor-associated macrophages (TAMs) are vital contributors to the growth, metastasis, and therapeutic resistance of various cancers, including hepatocellular carcinoma (HCC). However, the exact phenotype of TAMs and the mechanisms underlying their modulation for therapeutic purposes have not been determined. Here, we present compelling evidence that glutamine-derived aspartate in TAMs stimulates spermidine production through the polyamine synthesis pathway, thereby increasing the translation efficiency of HIF-1α via eIF5A hypusination. Consequently, augmented translation of HIF-1α drives TAMs to undergo an increase glycolysis and acquire a metabolic phenotype distinct from that of M2 macrophages. Finally, eIF5A levels in tumor stromal lesions were greater than those in nontumor stromal lesions. Additionally, a higher degree of tumor stromal eIF5A hypusination was significantly associated with a more advanced tumor stage. Taken together, these data highlight the potential of inhibiting hypusinated eIF5A by targeting glutamine metabolism in TAMs, thereby opening a promising avenue for the development of novel therapeutic approaches for HCC.

DOI: https://doi.org/10.1038/s12276-024-01214-1
Pancreas. 2024 May 01.

Screening of amino acids as a safe energy source for isolated rat pancreatic acini.

Anastasiia M Zub, Bohdan O Manko, Volodymyr V Manko.

OBJECTIVES: Amino acids play an essential role in protein synthesis, metabolism and survival of pancreatic acini. Adequate nutritional support is important for acute pancreatitis treatment. However, high concentrations of arginine and lysine may induce acute pancreatitis. The study aimed to identify the most suitable L-amino acids as safe energy sources for pancreatic acinar cells.METHODS: Pancreatic acini were isolated from male Wistar rats. Effects of amino acids (0.1-20 mM) on uncoupled respiration of isolated acini were studied with a Clark electrode. Cell death was evaluated with fluorescent microscopy and DNA gel electrophoresis.
RESULTS: Among the tested amino acids, glutamate, glutamine, alanine, lysine and aspartate were able to stimulate the uncoupled respiration rate of isolated pancreatic acini, while arginine, histidine and asparagine were not. Lysine, arginine and glutamine (20 mM) caused complete loss of plasma membrane integrity of acinar cells after 24 h of incubation. Glutamine also caused early (2-4 h) cell swelling and blebbing. Aspartate, asparagine and glutamate only moderately decreased the number of viable cells, while alanine and histidine were not toxic. DNA fragmentation assay and microscopic analysis of nuclei showed no evidence of apoptosis in cells treated with amino acids.
CONCLUSIONS: Alanine and glutamate are safe and effective energy sources for mitochondria of pancreatic acinar cells.

DOI: https://doi.org/10.1097/MPA.0000000000002350
Cancer Control. 2024 Jan-Dec;31:31 10732748241251583

L-type Amino Acid Transporter 1 as a Therapeutic Target in Pancreatic Cancer.

Ragnar Norrsell, Monika Bauden, Roland Andersson, Daniel Ansari.

  Metabolic rewiring is a key feature of cancer cells to support the demands of growth and proliferation. The metabolism of amino acids is altered in many cancers, including pancreatic cancer. The cellular uptake of amino acids is regulated by amino acid transporters, such as L-type amino acid transporter 1 (LAT1). Accumulating evidence suggests that LAT1 is overexpressed in pancreatic cancer and confers a poor prognosis. Here we discuss the prospects of utilizing LAT1 as a novel target for pancreatic cancer therapy.

Keywords:  LAT1; pancreatic cancer; prognosis; therapy

DOI:  https://doi.org/10.1177/10732748241251583
J Adv Res. 2024 Apr 25. pii: S2090-1232(24)00159-0. [Epub ahead of print]

Abnormal changes in metabolites caused by m6A methylation modification: The leading factors that induce the formation of immunosuppressive tumor microenvironment and their promising potential for clinical application.

Liang Zhao, Junchen Guo, Shasha Xu, Meiqi Duan, Baiming Liu, He Zhao, Yihan Wang, Haiyang Liu, Zhi Yang, Hexue Yuan, Xiaodi Jiang, Xiaofeng Jiang.

  BACKGROUND: N6-methyladenosine (m6A) RNA methylation modifications have been widely implicated in the metabolic reprogramming of various cell types within the tumor microenvironment (TME) and are essential for meeting the demands of cellular growth and maintaining tissue homeostasis, enabling cells to adapt to the specific conditions of the TME. An increasing number of research studies have focused on the role of m6A modifications in glucose, amino acid and lipid metabolism, revealing their capacity to induce aberrant changes in metabolite levels. These changes may in turn trigger oncogenic signaling pathways, leading to substantial alterations within the TME. Notably, certain metabolites, including lactate, succinate, fumarate, 2-hydroxyglutarate (2-HG), glutamate, glutamine, methionine, S-adenosylmethionine, fatty acids and cholesterol, exhibit pronounced deviations from normal levels. These deviations not only foster tumorigenesis, proliferation and angiogenesis but also give rise to an immunosuppressive TME, thereby facilitating immune evasion by the tumor.AIM OF REVIEW: The primary objective of this review is to comprehensively discuss the regulatory role of m6A modifications in the aforementioned metabolites and their potential impact on the development of an immunosuppressive TME through metabolic alterations.
KEY SCIENTIFIC CONCEPTS OF REVIEW: This review aims to elaborate on the intricate networks governed by the m6A-metabolite-TME axis and underscores its pivotal role in tumor progression. Furthermore, we delve into the potential implications of the m6A-metabolite-TME axis for the development of novel and targeted therapeutic strategies in cancer research.

Keywords:  Cancer; Metabolites; Targeted therapy; Tumor immunosuppressive microenvironment; m(6)A

DOI:  https://doi.org/10.1016/j.jare.2024.04.016
Front Immunol. 2024 ;15 1381970

Targeting metabolism of breast cancer and its implications in T cell immunotherapy.

Jialuo Zou, Cunjun Mai, Zhiqin Lin, Jian Zhou, Guie Lai.

  Breast cancer is a prominent health issue amongst women around the world. Immunotherapies including tumor targeted antibodies, adoptive T cell therapy, vaccines, and immune checkpoint blockers have rejuvenated the clinical management of breast cancer, but the prognosis of patients remains dismal. Metabolic reprogramming and immune escape are two important mechanisms supporting the progression of breast cancer. The deprivation uptake of nutrients (such as glucose, amino acid, and lipid) by breast cancer cells has a significant impact on tumor growth and microenvironment remodeling. In recent years, in-depth researches on the mechanism of metabolic reprogramming and immune escape have been extensively conducted, and targeting metabolic reprogramming has been proposed as a new therapeutic strategy for breast cancer. This article reviews the abnormal metabolism of breast cancer cells and its impact on the anti-tumor activity of T cells, and further explores the possibility of targeting metabolism as a therapeutic strategy for breast cancer.

Keywords:  T cell immunotherapy; amino acid; breast cancer; glucose; immune escape; lipid; metabolic reprogramming

DOI:  https://doi.org/10.3389/fimmu.2024.1381970
Cell Metab. 2024 Apr 24. pii: S1550-4131(24)00130-X. [Epub ahead of print]

Dietary intake and glutamine-serine metabolism control pathologic vascular stiffness.

Nesrine S Rachedi, Ying Tang, Yi-Yin Tai, Jingsi Zhao, Caroline Chauvet, Julien Grynblat, Kouamé Kan Firmin Akoumia, Leonard Estephan, Stéphanie Torrino, Chaima Sbai, Amel Ait-Mouffok, Joseph D Latoche, Yassmin Al Aaraj, Frederic Brau, Sophie Abélanet, Stephan Clavel, Yingze Zhang, Christelle Guillermier, Naveen V G Kumar, Sina Tavakoli, Olaf Mercier, Michael G Risbano, Zhong-Ke Yao, Guangli Yang, Ouathek Ouerfelli, Jason S Lewis, David Montani, Marc Humbert, Matthew L Steinhauser, Carolyn J Anderson, William M Oldham, Frédéric Perros, Thomas Bertero, Stephen Y Chan.

  Perivascular collagen deposition by activated fibroblasts promotes vascular stiffening and drives cardiovascular diseases such as pulmonary hypertension (PH). Whether and how vascular fibroblasts rewire their metabolism to sustain collagen biosynthesis remains unknown. Here, we found that inflammation, hypoxia, and mechanical stress converge on activating the transcriptional coactivators YAP and TAZ (WWTR1) in pulmonary arterial adventitial fibroblasts (PAAFs). Consequently, YAP and TAZ drive glutamine and serine catabolism to sustain proline and glycine anabolism and promote collagen biosynthesis. Pharmacologic or dietary intervention on proline and glycine anabolic demand decreases vascular stiffening and improves cardiovascular function in PH rodent models. By identifying the limiting metabolic pathways for vascular collagen biosynthesis, our findings provide guidance for incorporating metabolic and dietary interventions for treating cardiopulmonary vascular disease.

Keywords:  cardiovascular disease; collagen metabolism; fibrosis; glutamine metabolism; metabolism; nutrition; pulmonary hypertension; serine metabolism; vascular fibroblast

DOI:  https://doi.org/10.1016/j.cmet.2024.04.010
Biotechnol Appl Biochem. 2024 Apr 29.

Investigation of the effects of thiazole compounds on thioredoxin reductase 1 (TrxR1), glutathione S-transferase (GST), and glutathione reductase (GR) targeted human brain glioblastoma cancer (U-87 MG).

Işıl Nihan Korkmaz.

  Cancer is a fatal disease that kills thousands of people worldwide. Despite the information produced by research on cancer treatment, applications in cancer treatment are limited. Therefore, scientists' efforts to develop more effective treatment approaches continue. In the study, we aimed to determine the anticancer potential of amino thiazole compounds on human glioblastoma (U-87 MG) and human dermal fibroblast (HDFa) cells and their inhibition effects on enzymes that cause multidrug resistance in cancer cells. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide cell viability test was performed to understand the cytotoxic properties of thiazole derivatives. The cellular death mechanisms behind thiazole application were investigated using flow cytometry analysis. According to cell viability analysis, thiazole derivatives exhibited a greater effect on U-87 MG than the HDFa cell line in terms of cytotoxicity. Flow cytometry showed higher apoptotic cell death in U-87 MG cells than in the HDFa cell line. It can be concluded that thiazole compounds exert anticancer effects on U-87 MG and HDFa as well as show apoptotic properties. Their effects on thioredoxin reductase 1 (TrxR1), glutathione S-transferase (GST), and glutathione reductase (GR) activities, which are important in the development of chemotherapeutic methods, were also examined. From the results obtained, it was determined that the 2-amino-4-(p-tolyl)thiazole (T7) compound significantly suppressed both TrxR1 and GST activities, and the 2-amino-6-methylbenzothiazole (T8) compound significantly suppressed both TrxR1 and GST activities. Compound T7 was determined to be a selective inhibitor for TrxR1 and GST targeting, and compound T8 was determined to be a selective inhibitor for TrxR1 and GR targeting glioblastoma treatment.

Keywords:  cancer; enzyme; glutathione; multidrug resistance; thiazole

DOI:  https://doi.org/10.1002/bab.2589
Aging (Albany NY). 2024 Apr 26. 16

HCMMD: systematic evaluation of metabolites in body fluids as liquid biopsy biomarker for human cancers.

Xun Dong, Yaoyao Qu, Tongtong Sheng, Yuanming Fan, Silu Chen, Qinbo Yuan, Gaoxiang Ma, Yuqiu Ge.

  Metabolomics is a rapidly expanding field in systems biology used to measure alterations of metabolites and identify metabolic biomarkers in response to disease processes. The discovery of metabolic biomarkers can improve early diagnosis, prognostic prediction, and therapeutic intervention for cancers. However, there are currently no databases that provide a comprehensive evaluation of the relationship between metabolites and cancer processes. In this review, we summarize reported metabolites in body fluids across pan-cancers and characterize their clinical applications in liquid biopsy. We conducted a search for metabolic biomarkers using the keywords ("metabolomics" OR "metabolite") AND "cancer" in PubMed. Of the 22,254 articles retrieved, 792 were deemed potentially relevant for further review. Ultimately, we included data from 573,300 samples and 17,083 metabolic biomarkers. We collected information on cancer types, sample size, the human metabolome database (HMDB) ID, metabolic pathway, area under the curve (AUC), sensitivity and specificity of metabolites, sample source, detection method, and clinical features were collected. Finally, we developed a user-friendly online database, the Human Cancer Metabolic Markers Database (HCMMD), which allows users to query, browse, and download metabolite information. In conclusion, HCMMD provides an important resource to assist researchers in reviewing metabolic biomarkers for diagnosis and progression of cancers.

Keywords:  cancer; database; diagnostic biomarker; liquid biopsy; metabolites

DOI:  https://doi.org/10.18632/aging.205779