bims-glucam 2024-09-01 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2024–09–01
eightteen papers selected by
Sreeparna Banerjee, Middle East Technical University

The unique catalytic properties of PSAT1 mediate metabolic adaptation to glutamine blockade.
TFAP2A Activates S100A2 to Mediate Glutamine Metabolism and Promote Lung Adenocarcinoma Metastasis.
Self-assembled metal-polyphenolic based multifunctional nanomedicine to improve therapy treatment of pancreatic cancer by inhibition of glutamine metabolism.
Glutamine Metabolism and Prostate Cancer.
Phosphoenolpyruvate carboxykinase 2-mediated metabolism promotes lung tumorigenesis by inhibiting mitochondrial-associated apoptotic cell death.
Multidimensional analysis of tumor stem cells: from biological properties, metabolic adaptations to immune escape mechanisms.
Pyruvate Carboxylase Attenuates Myocardial Ischemia-Reperfusion Injury in Heart Transplantation via Wnt/β-Catenin-Mediated Glutamine Metabolism.
Amino acid metabolism in kidney health and disease.
Metabolite signaling in the heart.
Phosphoribosyl pyrophosphate amidotransferase: Novel biomarker and therapeutic target for nasopharyngeal carcinoma.
Metabolic landscape of human alveolar type II epithelial cells undergoing epithelial-mesenchymal transition induced directly by silica exposure.
An economic demand-based framework for prioritization strategies in response to transient amino acid limitations.
Naked mesoporous rhodium nanospheres with glutathione depletion and photothermal capabilities for tumor therapy.
Amino acid metabolism in glioma: in vivo MR-spectroscopic detection of alanine as a potential biomarker of poor survival in glioma patients.
Simultaneous detection of 10 cancer-associated amino acids and polyamines by high-performance liquid chromatography-high resolution mass spectrometry in pleural effusion cells obtained from lung adenocarcinoma patients.
Glutathione and viscosity double-locked response fluorescent probe for imaging and surgical navigation of hepatocellular carcinoma.
The role of metabolic reprogramming in immune escape of triple-negative breast cancer.
Glutathione transferase omega 1-1 (GSTO1-1) can effect the inter-cell transfer of cisplatin resistance through the exosomal route.

Nat Metab. 2024 Aug;6(8): 1529-1548

The unique catalytic properties of PSAT1 mediate metabolic adaptation to glutamine blockade.

Yijian Qiu, Olivia T Stamatatos, Qingting Hu, Jed Ruiter Swain, Suzanne Russo, Ava Sann, Ana S H Costa, Sara Violante, David L Spector, Justin R Cross, Michael J Lukey.

Cultured cancer cells frequently rely on the consumption of glutamine and its subsequent hydrolysis by glutaminase (GLS). However, this metabolic addiction can be lost in the tumour microenvironment, rendering GLS inhibitors ineffective in the clinic. Here we show that glutamine-addicted breast cancer cells adapt to chronic glutamine starvation, or GLS inhibition, via AMPK-mediated upregulation of the serine synthesis pathway (SSP). In this context, the key product of the SSP is not serine, but α-ketoglutarate (α-KG). Mechanistically, we find that phosphoserine aminotransferase 1 (PSAT1) has a unique capacity for sustained α-KG production when glutamate is depleted. Breast cancer cells with resistance to glutamine starvation or GLS inhibition are highly dependent on SSP-supplied α-KG. Accordingly, inhibition of the SSP prevents adaptation to glutamine blockade, resulting in a potent drug synergism that suppresses breast tumour growth. These findings highlight how metabolic redundancy can be context dependent, with the catalytic properties of different metabolic enzymes that act on the same substrate determining which pathways can support tumour growth in a particular nutrient environment. This, in turn, has practical consequences for therapies targeting cancer metabolism.

DOI: https://doi.org/10.1038/s42255-024-01104-w
Clin Respir J. 2024 Aug;18(8): e13825

TFAP2A Activates S100A2 to Mediate Glutamine Metabolism and Promote Lung Adenocarcinoma Metastasis.

Tao Zeng, Wangsheng Ren, Hang Zeng, Dachun Wang, Xianyu Wu, Guo Xu.

   BACKGROUND: Lung adenocarcinoma (LUAD) is a fatal disease with metabolic abnormalities. The dysregulation of S100 calcium-binding protein A2 (S100A2), a member of the S100 protein family, is connected to the development of various cancers. The impact of S100A2 on the LUAD occurrence and metastasis, however, has not yet been reported. The functional mechanism of S100A2 on LUAD cell metastasis was examined in this article.
METHODS: The expression of TFAP2A and S100A2 in LUAD tissues and cells was analyzed by bioinformatics and qRT-PCR, respectively. The enrichment pathway analysis was performed on S100A2. Bioinformatics analysis determined the binding relationship between TFAP2A and S100A2, and their interaction was validated through dual-luciferase and chromatin immunoprecipitation experiments. Cell viability was determined using cell counting kit-8 (CCK-8). A transwell assay was performed to analyze the invasion and migration of cells. Immunofluorescence was conducted to obtain vimentin and E-cadherin expression, and a western blot was used to detect the expression of MMP-2, MMP-9, GLS, and GLUD1. The kits measured the NADPH/NADP ratio, glutathione (GSH)/glutathione disulfide (GSSG) levels, and the contents of glutamine, α-KG, and glutamate.
RESULTS: S100A2 was upregulated in LUAD tissues and cells, and S100A2 mediated glutamine metabolism to induce LUAD metastasis. Additionally, the transcriptional regulator TFAP2A was discovered upstream of S100A2, and TFAP2A expression was upregulated in LUAD, which indicated that TFAP2A promoted the S100A2 expression. The rescue experiment found that upregulation of S100A2 could reverse the inhibitory effects of silencing TFAP2A on glutamine metabolism and cell metastasis.
CONCLUSION: In conclusion, by regulating glutamine metabolism, the TFAP2A/S100A2 axis facilitated LUAD metastasis. This suggested that targeting S100A2 could be beneficial for LUAD treatment.

Keywords:  S100A2; TFAP2A; glutamine metabolism; lung adenocarcinoma; metastasis

DOI:  https://doi.org/10.1111/crj.13825
Colloids Surf B Biointerfaces. 2024 Aug 13. pii: S0927-7765(24)00421-1. [Epub ahead of print]244 114162

Self-assembled metal-polyphenolic based multifunctional nanomedicine to improve therapy treatment of pancreatic cancer by inhibition of glutamine metabolism.

Yiwei Dai, Jieru Li, Tao Wang, Xinyu Zhang, Pengcheng Du, Yuman Dong, Zuoyi Jiao.

  Cancer poses a significant threat to human health and life. Chemotherapy, immunotherapy and chemodynamic therapy (CDT) are effective treatments for cancer. However, the presence of metabolic reprogramming via glutamine in tumor cells limits their therapeutic effectiveness. Herein, we propose an effective assembly strategy to synthesize a novel metal-polyphenolic based multifunctional nanomedicine (Fe-DBEF) containing Pluronic F127 stable ferric ion crosslinked epigallocatechin gallate (EGCG) nanoparticles loaded with GLS1 inhibitor bis-2-(5-phenylacetamino-1,3,4-thiadiazole-2-yl) ethyl sulfide (BPTES) and chemotherapy drug doxorubicin (DOX). Our study demonstrates that Fe-DBEF nanomedicine exhibits high efficiency anti-proliferation properties in pancreatic cancer through a combination of in vitro cell experiments, human organoid experiments and KPC animal experiments. Notably, Fe-DBEF nanomedicine can reduce the production of glutathione (GSH) in tumor cells, thereby reducing their resistance to ROS therapy. Additionally, excessive ROS production also aggravates DNA damage caused by DOX, synergistically sensitizing chemotherapy and promoting apoptosis for efficient treatment of pancreatic cancer. Overall, our findings suggest that inhibiting glutamine metabolism to increase the sensitivity of chemotherapy/CDT using metal-polyphenolic based multifunctional nanomedicine provides a promising combination of multiple therapeutic means for treating pancreatic cancer.

Keywords:  Chemodynamic therapy; Chemotherapy; Glutaminase inhibitors; Nanomedicine; Tumor metabolism

DOI:  https://doi.org/10.1016/j.colsurfb.2024.114162
Cancers (Basel). 2024 Aug 18. pii: 2871. [Epub ahead of print]16(16):

Glutamine Metabolism and Prostate Cancer.

Holger H H Erb, Nikita Polishchuk, Oleh Stasyk, Uğur Kahya, Matthias M Weigel, Anna Dubrovska.

  Glutamine (Gln) is a non-essential amino acid that is involved in the development and progression of several malignancies, including prostate cancer (PCa). While Gln is non-essential for non-malignant prostate epithelial cells, PCa cells become highly dependent on an exogenous source of Gln. The Gln metabolism in PCa is tightly controlled by well-described oncogenes such as MYC, AR, and mTOR. These oncogenes contribute to therapy resistance and progression to the aggressive castration-resistant PCa. Inhibition of Gln catabolism impedes PCa growth, survival, and tumor-initiating potential while sensitizing the cells to radiotherapy. Therefore, given its significant role in tumor growth, targeting Gln metabolism is a promising approach for developing new therapeutic strategies. Ongoing clinical trials evaluate the safety and efficacy of Gln catabolism inhibitors in combination with conventional and targeted therapies in patients with various solid tumors, including PCa. Further understanding of how PCa cells metabolically interact with their microenvironment will facilitate the clinical translation of Gln inhibitors and help improve therapeutic outcomes. This review focuses on the role of Gln in PCa progression and therapy resistance and provides insights into current clinical trials.

Keywords:  androgen receptor; chemotherapy; glutamine; prostate cancer; radiation therapy; therapy resistance

DOI:  https://doi.org/10.3390/cancers16162871
Front Pharmacol. 2024 ;15 1434988

Phosphoenolpyruvate carboxykinase 2-mediated metabolism promotes lung tumorigenesis by inhibiting mitochondrial-associated apoptotic cell death.

Jing Zhang, Wenjuan He, Dongmei Liu, Wenyu Zhang, Huan Qin, Song Zhang, Ailan Cheng, Qiang Li, Feilong Wang.

   Background: It is unknown how cancer cells override apoptosis and maintain progression under nutrition-deprived conditions within the tumor microenvironment. Phosphoenolpyruvate carboxykinase (PEPCK or PCK) catalyzes the first rate-limiting reaction in gluconeogenesis, which is an essential metabolic alteration that is required for the proliferation of cancer cells under glucose-limited conditions. However, if PCK-mediated gluconeogenesis affects apoptotic cell death of non small cell lung cancer (NSCLC) and its potential mechanisms remain unknown.
Methods: RNA-seq, Western blot and RT-PCR were performed in A549 cell lines cultured in medium containing low or high concentrations of glucose (1 mM vs. 20 mM) to gain insight into how cancer cells rewire their metabolism under glucose-restriction conditions. Stable isotope tracing metabolomics technology (LC-MS) was employed to allow precise quantification of metabolic fluxes of the TCA cycle regulated by PCK2. Flow Cytometry was used to assess the rates of early and later apoptosis and mitochondrial ROS in NSCLC cells. Transwell assays and luciferase-based in vivo imaging were used to determine the role of PCK2 in migration and invasion of NSCLC cells. Xenotransplants on BALB/c nude mice to evaluate the effects of PCK2 on tumor growth in vivo. Western blot, Immunohistochemistry and TUNEL assays to evaluate the protein levels of mitochondrial apoptosis.
Results: This study report that the mitochondrial resident PCK (PCK2) is upregulated in dependent of endoplasmic reticulum stress-induced expression of activating transcription factor 4 (ATF4) upon glucose deprivation in NSCLC cells. Further, the study finds that PCK2-mediated metabolism is required to decrease the burden of the TCA cycles and oxidative phosphorylation as well as the production of mitochondrial reactive oxygen species. These metabolic alterations in turn reduce the activation of Caspase9-Caspase3-PARP signal pathway which drives apoptotic cell death. Importantly, silencing PCK2 increases apoptosis of NSCLC cells under low glucose condition and inhibits tumor growth both in vitro and in vivo.
Conclusion: In summary, PCK2-mediated metabolism is an important metabolic adaptation for NSCLC cells to acquire resistance to apoptosis under glucose deprivation.

Keywords:  lung tumorigenesis; metabolic reprogramming; mitochondrial apoptosis; phosphoenolpyruvate carboxykinase 2; reactive oxygen species

DOI:  https://doi.org/10.3389/fphar.2024.1434988
Front Cell Dev Biol. 2024 ;12 1441081

Multidimensional analysis of tumor stem cells: from biological properties, metabolic adaptations to immune escape mechanisms.

Han Han, Ting He, Yingfan Wu, Tianmei He, Weiqiang Zhou.

  As a key factor in tumorigenesis, progression, recurrence and metastasis, the biological properties, metabolic adaptations and immune escape mechanisms of CSCs are the focus of current oncological research. CSCs possess self-renewal, multidirectional differentiation and tumorigenicity, and their mechanisms of action can be elucidated by the clonal evolution, hierarchical model and the dynamic CSCs model, of which the dynamic model is widely recognized due to its better explanation of the function and origin of CSCs. The origin hypothesis of CSCs involves cell-cell fusion, horizontal gene transfer, genomic instability and microenvironmental regulation, which together shape the diversity of CSCs. In terms of classification, CSCs include primary CSCs (pri-CSCs), precancerous stem cells (pre-CSCs), migratory CSCs (mig-CSCs), and chemo-radiotherapy-resistant CSCs (cr-CSCs and rr-CSCs), with each type playing a specific role in tumor progression. Surface markers of CSCs, such as CD24, CD34, CD44, CD90, CD133, CD166, EpCAM, and LGR5, offer the possibility of identifying, isolating, and targeting CSCs, but the instability and heterogeneity of their expression increase the difficulty of treatment. CSCs have adapted to their survival needs through metabolic reprogramming, showing the ability to flexibly switch between glycolysis and oxidative phosphorylation (OXPHOS), as well as adjustments to amino acid and lipid metabolism. The Warburg effect typifies their metabolic profiles, and altered glutamine and fatty acid metabolism further contributes to the rapid proliferation and survival of CSCs. CSCs are able to maintain their stemness by regulating the metabolic networks to maintain their stemness characteristics, enhance antioxidant defences, and adapt to therapeutic stress. Immune escape is another strategy for CSCs to maintain their survival, and CSCs can effectively evade immune surveillance through mechanisms such as up-regulating PD-L1 expression and promoting the formation of an immunosuppressive microenvironment. Together, these properties reveal the multidimensional complexity of CSCs, underscoring the importance of a deeper understanding of the biology of CSCs for the development of more effective tumor therapeutic strategies. In the future, therapies targeting CSCs will focus on precise identification of surface markers, intervention of metabolic pathways, and overcoming immune escape, with the aim of improving the relevance and efficacy of cancer treatments, and ultimately improving patient prognosis.

Keywords:  PD-L1; biological properties; immune escape; metabolic remodeling; tumor stem cells

DOI:  https://doi.org/10.3389/fcell.2024.1441081
Biomedicines. 2024 Aug 12. pii: 1826. [Epub ahead of print]12(8):

Pyruvate Carboxylase Attenuates Myocardial Ischemia-Reperfusion Injury in Heart Transplantation via Wnt/β-Catenin-Mediated Glutamine Metabolism.

Zihao Wang, Hongwen Lan, Yixuan Wang, Qiang Zheng, Chenghao Li, Kan Wang, Tixiusi Xiong, Qingping Wu, Nianguo Dong.

  The ischemia-reperfusion process of a donor heart during heart transplantation leads to severe mitochondrial dysfunction, which may be the main cause of donor heart dysfunction after heart transplantation. Pyruvate carboxylase (PC), an enzyme found in mitochondria, is said to play a role in the control of oxidative stress and the function of mitochondria. This research examined the function of PC and discovered the signaling pathways controlled by PC in myocardial IRI. We induced IRI using a murine heterotopic heart transplantation model in vivo and a hypoxia-reoxygenation cell model in vitro and evaluated inflammatory responses, oxidative stress levels, mitochondrial function, and cardiomyocyte apoptosis. In both in vivo and in vitro settings, we observed a significant decrease in PC expression during myocardial IRI. PC knockdown aggravated IRI by increasing MDA content, LDH activity, TUNEL-positive cells, serum cTnI level, Bax protein expression, and the level of inflammatory cytokines and decreasing SOD activity, GPX activity, and Bcl-2 protein expression. PC overexpression yielded the opposite findings. Additional research indicated that reducing PC levels could block the Wnt/β-catenin pathway and glutamine metabolism by hindering the movement of β-catenin to the nucleus and reducing the activity of complex I and complex II, as well as ATP levels, while elevating the ratios of NADP+/NADPH and GSSG/GSH. Overall, the findings indicated that PC therapy can shield the heart from IRI during heart transplantation by regulating glutamine metabolism through the Wnt/β-catenin pathway.

Keywords:  Wnt/β-catenin pathway; glutamine metabolism; heart transplantation; ischemia–reperfusion injury; pyruvate carboxylase

DOI:  https://doi.org/10.3390/biomedicines12081826
Nat Rev Nephrol. 2024 Aug 28.

Amino acid metabolism in kidney health and disease.

Martine G E Knol, Vera C Wulfmeyer, Roman-Ulrich Müller, Markus M Rinschen.

Amino acids form peptides and proteins and are therefore considered the main building blocks of life. The kidney has an important but under-appreciated role in the synthesis, degradation, filtration, reabsorption and excretion of amino acids, acting to retain useful metabolites while excreting potentially harmful and waste products from amino acid metabolism. A complex network of kidney transporters and enzymes guides these processes and moderates the competing concentrations of various metabolites and amino acid products. Kidney amino acid metabolism contributes to gluconeogenesis, nitrogen clearance, acid-base metabolism and provision of fuel for tricarboxylic acid cycle and urea cycle intermediates, and is thus a central hub for homeostasis. Conversely, kidney disease affects the levels and metabolism of a variety of amino acids. Here, we review the metabolic role of the kidney in amino acid metabolism and describe how different diseases of the kidney lead to aberrations in amino acid metabolism. Improved understanding of the metabolic and communication routes that are affected by disease could provide new mechanistic insights into the pathogenesis of kidney diseases and potentially enable targeted dietary or pharmacological interventions.

DOI: https://doi.org/10.1038/s41581-024-00872-8
Nat Cardiovasc Res. 2023 Jun;2(6): 504-516

Metabolite signaling in the heart.

Emily Flam, Zolt Arany.

The heart is the most metabolically active organ in the body, sustaining a continuous and high flux of nutrient catabolism via oxidative phosphorylation. The nature and relative contribution of these fuels have been studied extensively for decades. By contrast, less attention has been placed on how intermediate metabolites generated from this catabolism affect intracellular signaling. Numerous metabolites, including intermediates of glycolysis and the tricarboxylic acid (TCA) cycle, nucleotides, amino acids, fatty acids and ketones, are increasingly appreciated to affect signaling in the heart, via various mechanisms ranging from protein-metabolite interactions to modifying epigenetic marks. We review here the current state of knowledge of intermediate metabolite signaling in the heart.

DOI: https://doi.org/10.1038/s44161-023-00270-6
Cancer Sci. 2024 Aug 28.

Phosphoribosyl pyrophosphate amidotransferase: Novel biomarker and therapeutic target for nasopharyngeal carcinoma.

Yuki Kitagawa, Satoru Kondo, Masaki Fukuyo, Kousho Wakae, Hirotomo Dochi, Harue Mizokami, Shigetaka Komura, Eiji Kobayashi, Nobuyuki Hirai, Takayoshi Ueno, Yosuke Nakanishi, Kazuhira Endo, Hisashi Sugimoto, Naohiro Wakisaka, Atsushi Kaneda, Tomokazu Yoshizaki.

  Cancer cells show a dynamic metabolic landscape, requiring a sufficient supply of nucleotides to proliferate. They are highly dependent on de novo purine biosynthetic pathways for their nucleotide requirements. Phosphoribosyl pyrophosphate amidotransferase (PPAT), catalyzing the first step of de novo purine biosynthesis, is highly expressed in various cancers. We observed an increased expression of PPAT in nasopharyngeal carcinoma (NPC). Moreover, our ribonucleic acid sequencing analysis showed high PPAT expression in Epstein-Barr virus-positive NPC, which was supported by in vitro analysis. Through a gene knockdown study, we showed that the suppression of PPAT expression reduced the proliferation and invasion of NPC cells. We also demonstrated the regulation of PPAT by glutamine, a cosubstrate for PPAT. A glutamine antagonist, 6-diazo-5-oxo-L-norleucine, blocked glutamine-mediated induction of PPAT and reduced NPC cell proliferation. Immunohistochemical analysis of PPAT in NPC tissues revealed increased expression of PPAT with disease progression, which was significantly associated with poor prognosis. In summary, this study highlighted the biological function of PPAT in NPC, establishing its potential as a novel prognostic biomarker for aggressive NPC and a promising therapeutic target.

Keywords:  Epstein–Barr virus; PPAT; glutamine; nasopharyngeal carcinoma; purine biosynthesis

DOI:  https://doi.org/10.1111/cas.16314
J Environ Sci (China). 2025 Mar;pii: S1001-0742(24)00108-6. [Epub ahead of print]149 676-687

Metabolic landscape of human alveolar type II epithelial cells undergoing epithelial-mesenchymal transition induced directly by silica exposure.

Jin Sun, Na Zhao, Ruijia Zhang, Yizheng Li, Tiantian Yu, Qiying Nong, Li Lin, Xubin Yang, Tiangang Luan, Baowei Chen, Yongshun Huang.

  Epithelial-mesenchymal transition (EMT) plays an irreplaceable role in the development of silicosis. However, molecular mechanisms of EMT induced by silica exposure still remain to be addressed. Herein, metabolic profiles of human alveolar type II epithelial cells (A549 cells) exposed directly to silica were characterized using non-targeted metabolomic approaches. A total of 84 differential metabolites (DMs) were identified in silica-treated A549 cells undergoing EMT, which were mainly enriched in metabolisms of amino acids (e.g., glutamate, alanine, aspartate), purine metabolism, glycolysis, etc. The number of DMs identified in the A549 cells obviously increased with the elevated exposure concentration of silica. Remarkably, glutamine catabolism was significantly promoted in the silica-treated A549 cells, and the levels of related metabolites (e.g., succinate) and enzymes (e.g., α-ketoglutarate (α-KG) dehydrogenase) were substantially up-regulated, with a preference to α-KG pathway. Supplementation of glutamine into the cell culture could substantially enhance the expression levels of both EMT-related markers and Snail (zinc finger transcription factor). Our results suggest that the EMT of human alveolar epithelial cells directly induced by silica can be essential to the development of silicosis.

Keywords:  Epithelial-mesenchymal transition (EMT); Glutamine; Human alveolar type II epithelial cells (ATII cells); Metabolomics; Silica exposure

DOI:  https://doi.org/10.1016/j.jes.2024.02.020
Nat Commun. 2024 Aug 23. 15(1): 7254

An economic demand-based framework for prioritization strategies in response to transient amino acid limitations.

Ritu Gupta, Swagata Adhikary, Nidhi Dalpatraj, Sunil Laxman.

Cells contain disparate amounts of distinct amino acids, each of which has different metabolic and chemical origins, but the supply cost vs demand requirements of each is unclear. Here, using yeast we quantify the restoration-responses after disrupting amino acid supply, and uncover a hierarchically prioritized restoration strategy for distinct amino acids. We comprehensively calculate individual amino acid biosynthetic supply costs, quantify total demand for an amino acid, and estimate cumulative supply/demand requirements for each amino acid. Through this, we discover that the restoration priority is driven by the gross demand for an amino acid, which is itself coupled to low supply costs for that amino acid. Demand from metabolic requirements dominate the demand-pulls for an amino acid, as exemplified by the largest restoration response upon disrupting arginine supply. Collectively, this demand-driven framework that drives the amino acid economy can identify novel amino acid responses, and help design metabolic engineering applications.

DOI: https://doi.org/10.1038/s41467-024-51769-w
J Colloid Interface Sci. 2024 Aug 13. pii: S0021-9797(24)01861-7. [Epub ahead of print]677(Pt B): 1075-1083

Naked mesoporous rhodium nanospheres with glutathione depletion and photothermal capabilities for tumor therapy.

Haixiang Wang, Hongwei Wang, Gaoyuan Yu, Lijuan Xie, Cong Zhang, Chao Xu, Xiaopeng Ma, Zhaohua Miao, Yue Yu.

  Pancreatic and colon cancer are malignant tumors of the digestive system that currently lack effective treatments. In cancer cells, a high level of glutathione (GSH) is indispensable to scavenge excessive reactive oxygen species (ROS) and detoxify xenobiotics, which make it a potential target for cancer therapy. GSH depletion has been proved to improve the therapeutic efficacy of photodynamic therapy. Here, we reported that naked mesoporous rhodium nanospheres (Rh MNs), prepared by soft template redox method, can act as GSH depletion agent and photothermal conversion agent to achieve synergistic therapy respectively. Different from conventional nanoagents, Rh MNs with the characteristics of easy synthesis, simple structure and multiple functions can decrease the GSH level in tumor and depict excellent photothermal ability with a high photothermal conversion efficiency (PTCE) up to 39%. Notably, multiple anti-tumor mechanisms in CT26 and BxPC-3 tumor models, include inhibited anti-apoptosis, DNA replication repair, and GSH synthesis are revealed, and the pancreatic tumor cure rate of the cooperative treatment group is 80%. Collectively, we developed Rh MNs to combine GSH depletion with photothermal therapy for cancer treatment.

Keywords:  Colon cancer; GSH depletion; Mesoporous nanospheres; Rhodium nanoparticles, pancreatic cancer

DOI:  https://doi.org/10.1016/j.jcis.2024.08.079
J Neurooncol. 2024 Aug 27.

Amino acid metabolism in glioma: in vivo MR-spectroscopic detection of alanine as a potential biomarker of poor survival in glioma patients.

Seyma Alcicek, Ulrich Pilatus, Andrei Manzhurtsev, Katharina J Weber, Michael W Ronellenfitsch, Joachim P Steinbach, Elke Hattingen, Katharina J Wenger.

   PURPOSE: Reprogramming of amino acid metabolism is relevant for initiating and fueling tumor formation and growth. Therefore, there has been growing interest in anticancer therapies targeting amino acid metabolism. While developing personalized therapeutic approaches to glioma, in vivo proton magnetic resonance spectroscopy (MRS) is a valuable tool for non-invasive monitoring of tumor metabolism. Here, we evaluated MRS-detected brain amino acids and myo-inositol as potential diagnostic and prognostic biomarkers in glioma.
METHOD: We measured alanine, glycine, glutamate, glutamine, and myo-inositol in 38 patients with MRI-suspected glioma using short and long echo-time single-voxel PRESS MRS sequences. The detectability of alanine, glycine, and myo-inositol and the (glutamate + glutamine)/total creatine ratio were evaluated against the patients' IDH mutation status, CNS WHO grade, and overall survival.
RESULTS: While the detection of alanine and non-detection of myo-inositol significantly correlated with IDH wildtype (p = 0.0008, p = 0.007, respectively) and WHO grade 4 (p = 0.01, p = 0.04, respectively), glycine detection was not significantly associated with either. The ratio of (glutamate + glutamine)/total creatine was significantly higher in WHO grade 4 than in 2 and 3. We found that the overall survival was significantly shorter in glioma patients with alanine detection (p = 0.00002).
CONCLUSION: Focusing on amino acids in MRS can improve its diagnostic and prognostic value in glioma. Alanine, which is visible at long TE even in the presence of lipids, could be a relevant indicator for overall survival.

Keywords:  Alanine; Amino acid metabolism; Gliomas; IDH mutation; Magnetic resonance spectroscopy; Overall survival

DOI:  https://doi.org/10.1007/s11060-024-04803-2
J Pharm Biomed Anal. 2024 Aug 14. pii: S0731-7085(24)00458-8. [Epub ahead of print]251 116418

Simultaneous detection of 10 cancer-associated amino acids and polyamines by high-performance liquid chromatography-high resolution mass spectrometry in pleural effusion cells obtained from lung adenocarcinoma patients.

Tingting Wang, Yina Pan, Xiuhong Hu, Wenbo Ren, Li Li, Jing Huang.

  The deregulation of amino acid and polyamine metabolism is a hallmark of malignancy that regulates cancer cell proliferation, angiogenesis, and invasion. A sensitive mass spectrometry method was developed to simultaneously quantify 10 cancer-associated metabolites in pleural effusion cells for the diagnosis of malignancy and to complement conventional pleural cytology. Analytes were detected by high-performance liquid chromatography-high resolution mass spectrometry (HPLC-HRMS) using C8-reversed-phase HPLC for separation and sequential window acquisition of all theoretical fragment ion spectra (SWATH) acquisition for obtaining high-resolution quantitative MS/MS chromatograms. This method was validated and applied to pleural effusion cells from patients with lung adenocarcinoma (LUAD, n = 48) and those from benign controls (n = 23). The range of the above metabolites was 2-200 ng/mL for proline, aspartate, ornithine, creatine, glutamine, glutamate, arginine, citrulline, and spermine and 10-1000 ng/mL for putrescine. The intra-assay and inter-assay coefficient of variation was below 13.70 % for all analytes. The joint detection of these metabolites in pleural effusion cells achieved a clinical sensitivity of 75.0 % and specificity of 95.7 % differentiating LUAD patients from benign controls. This assay enabled the detection of 10 cancer-associated metabolites in pleural effusion cells, and the increased concentration of these metabolites was correlated with the presence of LUAD.

Keywords:  Cancer-associated metabolites; High-performance liquid chromatography-high resolution mass spectrometry; Lung adenocarcinoma; Pleural effusion

DOI:  https://doi.org/10.1016/j.jpba.2024.116418
Chem Commun (Camb). 2024 Aug 27.

Glutathione and viscosity double-locked response fluorescent probe for imaging and surgical navigation of hepatocellular carcinoma.

Wen Zhang, Min Zhang, Mengmei Li, Xin Wang, Ping Li, Bo Tang.

Early diagnosis and precise treatment of hepatocellular carcinoma (HCC) are crucial for human health. Therefore, addressing the potential markers of HCC, glutathione (GSH) and viscosity, we constructed a fluorescent probe (PG-V) activated cascadically by GSH/viscosity. PG-V possessed excellent photophysical properties and biocompatibility, and could specifically illuminate tumor tissue, achieving fluorescence imaging of HCC, and imaging-guided tumor resection.

DOI: https://doi.org/10.1039/d4cc03582h
Front Immunol. 2024 ;15 1424237

The role of metabolic reprogramming in immune escape of triple-negative breast cancer.

Ruochen Bao, Hongtao Qu, Baifeng Li, Kai Cheng, Yandong Miao, Jiangtao Wang.

  Triple-negative breast cancer (TNBC) has become a thorny problem in the treatment of breast cancer because of its high invasiveness, metastasis and recurrence. Although immunotherapy has made important progress in TNBC, immune escape caused by many factors, especially metabolic reprogramming, is still the bottleneck of TNBC immunotherapy. Regrettably, the mechanisms responsible for immune escape remain poorly understood. Exploring the mechanism of TNBC immune escape at the metabolic level provides a target and direction for follow-up targeting or immunotherapy. In this review, we focus on the mechanism that TNBC affects immune cells and interstitial cells through hypoxia, glucose metabolism, lipid metabolism and amino acid metabolism, and changes tumor metabolism and tumor microenvironment. This will help to find new targets and strategies for TNBC immunotherapy.

Keywords:  amino acid metabolism; glucose metabolism; hypoxia; immune escape; lipid metabolism; triple-negative breast cancer

DOI:  https://doi.org/10.3389/fimmu.2024.1424237
Free Radic Biol Med. 2024 Aug 26. pii: S0891-5849(24)00626-9. [Epub ahead of print]

Glutathione transferase omega 1-1 (GSTO1-1) can effect the inter-cell transfer of cisplatin resistance through the exosomal route.

Simona Piaggi, Giulia Paties Montagner, Evelina Lorenzini, Matilde Masini, Vincenzo De Tata, Alfonso Pompella, Alessandro Corti.

  Glutathione transferase omega-1-1 (GSTO1-1) is a member of the glutathione transferase superfamily (GSTs) involved in the modulation of cell survival, proliferation and metabolism. Increased levels of GSTO1-1 have been associated with cancer progression and chemoresistance in different types of cancer cells, possibly supported by the post-traslational regulation of some major prosurvival pathways regulated by the enzyme. Our data demonstrate for the first time that GSTO1-1 can be released by cancer cells through the exosomal route and transferred to GSTO1-1 knock-out cells, this resulting in an increased resistance against cisplatin toxicity in recipient cells. The use the exosomal route to transfer the regulatory competences of GSTO1-1 could be a further element supporting its role in neoplastic progression.

Keywords:  Glutathione transferase omega-1-1; cisplatin; exosomes

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.08.032