bims-glucam 2024-09-15 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2024–09–15
nineteen papers selected by
Sreeparna Banerjee, Middle East Technical University

Glutamine metabolism promotes human trophoblast cell invasion via COL1A1 mediated by PI3K-AKT pathway.
NUAKs promote mTOR/c-Myc-induced glucose and glutamine reprogramming for cell growth and metastasis in breast cancer cells.
Prostate Cancer's Silent Partners: Fibroblasts and Their Influence on Glutamine Metabolism Manipulation.
Mitochondrial reprogramming by activating OXPHOS via glutamine metabolism in African American patients with bladder cancer.
Rewired glutamate metabolism diminishes cytostatic action of L-asparaginase.
ASCT2 Regulates Fatty Acid Metabolism to Trigger Glutamine Addiction in Basal-like Breast Cancer.
Cancer knocks you out by fasting: Cachexia as a consequence of metabolic alterations in cancer.
Oxidative stress promotes oral carcinogenesis via Thbs1-mediated M1-like tumor-associated macrophages polarization.
Glutaminolysis provides nucleotides and amino acids to regulate osteoclast differentiation in mice.
IRF5 mediates adaptive immunity via altered glutamine metabolism, mTORC1 signaling and post-transcriptional regulation following T cell receptor activation.
V9302-loaded copper-polyphenol hydrogel for enhancing the anti-tumor effect of disulfiram.
Causal relationship between circulating glutamine levels and idiopathic pulmonary fibrosis: a two-sample mendelian randomization study.
Cortisol affects macrophage polarization by inducing miR-143/145 cluster to reprogram glucose metabolism and by promoting TCA cycle anaplerosis.
Unraveling the Mystery of Energy-Sensing Enzymes and Signaling Pathways in Tumorigenesis and Their Potential as Therapeutic Targets for Cancer.
Specific inhibitory effects of exogenous d-Aspartate on the proliferation of intestinal epithelial cells.
Glutamine synthetase staining patterns in cirrhosis.
Multiomics reveals microbial metabolites as key actors in intestinal fibrosis in Crohn's disease.
Cu0-based nanoparticles boost anti-tumor efficacy via synergy of cuproptosis and ferroptosis enhanced by cuproptosis-induced glutathione synthesis disorder.
Disrupted glutamate homeostasis as a target for glioma therapy.

J Reprod Immunol. 2024 Aug 24. pii: S0165-0378(24)00130-X. [Epub ahead of print]166 104321

Glutamine metabolism promotes human trophoblast cell invasion via COL1A1 mediated by PI3K-AKT pathway.

Jialu Shi, Zhi Lin, Zimeng Zheng, Min Chen, Xu Huang, Jiarui Wang, Mingqing Li, Jun Shao.

  Abnormal trophoblast invasion function is an important cause of recurrent spontaneous abortion (RSA). Recent research has revealed a connection between glutamine metabolism and RSA. However, the interplay between these three factors and their related mechanisms remains unclear. To address this issue, we collected villus tissues from 10 healthy women with induced abortion and from 10 women with RSA to detect glutamine metabolism. Then, the trophoblast cell line HTR-8/SVneo was used in vitro to explore the effect of glutamine metabolism on trophoblast cells invasion, which was tested by transwell assay. We found that the concentration of glutamine in the villi of the normal pregnancy group was significantly higher than that in the RSA group. Correspondingly, the expression levels of key enzymes involved in glutamine synthesis and catabolism, including glutamine synthetase and glutaminase, were significantly higher in the villi of the normal pregnancy group. Regarding trophoblast cells, glutamine markedly enhanced the proliferative and invasive abilities of HTR-8/SVneo cells. Additionally, collagen type I alpha 1 (COL1A1) was confirmed to be a downstream target of glutamine, and glutamine also activated the PI3K-AKT pathway in HTR-8/SVneo cells. These findings indicate that glutamine metabolism facilitates the invasion of trophoblasts by up-regulating COL1A1 expression through the activation of the PI3K-AKT pathway, but the specific mechanism of COL1A1 requires further study.

Keywords:  COL1A1; Glutamine metabolism; PI3K-AKT pathway; Recurrent spontaneous abortion; Trophoblast invasion

DOI:  https://doi.org/10.1016/j.jri.2024.104321
Biochim Biophys Acta Mol Basis Dis. 2024 Sep 11. pii: S0925-4439(24)00502-7. [Epub ahead of print] 167508

NUAKs promote mTOR/c-Myc-induced glucose and glutamine reprogramming for cell growth and metastasis in breast cancer cells.

Acily Skadon Worral Wilfred Raj, Ravi Manoharan.

  Breast cancer progression and metastasis are closely connected to changes in glucose and glutamine metabolism. While Novel (nua) kinase family 1 (NUAK1) and Novel (nua) kinase family 2 (NUAK2), which are two members of the AMPK-related kinases, have been associated with breast tumorigenesis, their role in the metabolic reprogramming that occurs during breast cancer progression remains unclear. Our research uncovers that NUAKs expression is significantly higher in breast cancer tissues and cell lines, and it is positively related to glycolysis, the pentose phosphate pathway (PPP), glutamine metabolism, and a poor prognosis for breast cancer patients. We show that NUAKs significantly increase metabolic reprogramming, including aerobic glycolysis, PPP, and glutamine metabolism in triple negative breast cancer subtypes but only induce aerobic glycolysis and PPP in luminal breast cancer subtypes to meet the anabolic demands of rapidly dividing breast cancer cells. In contrast, the depletion of NUAKs has the opposite effect. Mechanistic insights reveal that NUAKs activate mammalian target of rapamycin (mTOR) signaling, which in turn upregulates the c-Myc transcription factor, a crucial regulator of glucose and glutamine metabolic gene expression. Moreover, we demonstrate that NUAKs enhance mTOR/c-Myc signaling pathways, leading to increased glucose and glutamine reprogramming, which supports rapid cell proliferation and metastatic potential in breast cancer cells. Importantly, pretreating breast cancer cells with mTOR inhibitors blocked the metabolic reprogramming and tumor-promoting effect of NUAK1/2. Therefore, targeting NUAKs may represent a novel therapeutic strategy for the treatment of breast cancer.

Keywords:  Breast cancer; Glucose reprogramming; Glutamine reprogramming; NUAKs; c-Myc; mTOR

DOI:  https://doi.org/10.1016/j.bbadis.2024.167508
Int J Mol Sci. 2024 Aug 27. pii: 9275. [Epub ahead of print]25(17):

Prostate Cancer's Silent Partners: Fibroblasts and Their Influence on Glutamine Metabolism Manipulation.

Pia V Hönscheid, Gustavo B Baretton, Martin Puhr, Tiziana Siciliano, Justus S Israel, Matthias B Stope, Celina Ebersbach, Alicia-Marie K Beier, Christian Thomas, Holger H H Erb.

  Cancer-associated fibroblast (CAF)s in the tumour microenvironment (TME) modulate the extracellular matrix, interact with cancer cells, and facilitate communication with infiltrating leukocytes, significantly contributing to cancer progression and therapeutic response. In prostate cancer (PCa), CAFs promote malignancy through metabolic rewiring, cancer stem cell regulation, and therapy resistance. Pre-clinical studies indicate that targeting amino acid metabolism, particularly glutamine (Gln) metabolism, reduces cancer proliferation and stemness. However, most studies lack the context of CAF-cancer interaction, focusing on monocultures. This study assesses the influence of CAFs on PCa growth by manipulating Gln metabolism using colour-labelled PCa cell lines (red) and fibroblast (green) in a co-culture system to evaluate CAFs' effects on PCa cell proliferation and clonogenic potential. CAFs increased the proliferation of hormone-sensitive LNCaP cells, whereas the castration-resistant C4-2 cells were unaffected. However, clonogenic growth increased in both cell lines. Gln deprivation and GLS1 inhibition experiments revealed that the increased growth rate of LNCAP cells was associated with increased dependence on Gln, which was confirmed by proteomic analyses. Tissue analysis of PCa patients revealed elevated GLS1 levels in both the PCa epithelium and stroma, suggesting that GLS1 is a therapeutic target. Moreover, the median overall survival analysis of GLS1 expression in the PCa epithelium and stroma identified a "high-risk" patient group that may benefit from GLS1-targeted therapies. Therefore, GLS1 targeting appears promising in castration-resistant PCa patients with high GLS1 epithelium and low GLS1 stromal expression.

Keywords:  PCa; cancer-associated fibroblasts; castration-resistant prostate cancer; hormone-sensitive prostate cancer; tumour microenvironment

DOI:  https://doi.org/10.3390/ijms25179275
JCI Insight. 2024 Sep 10. pii: e172336. [Epub ahead of print]9(17):

Mitochondrial reprogramming by activating OXPHOS via glutamine metabolism in African American patients with bladder cancer.

Karthik Reddy Kami Reddy, Danthasinghe Waduge Badrajee Piyarathna, Jun Hyoung Park, Vasanta Putluri, Chandra Sekhar Amara, Abu Hena Mostafa Kamal, Jun Xu, Daniel Kraushaar, Shixia Huang, Sung Yun Jung, Livia S Eberlin, Jabril R Johnson, Rick A Kittles, Leomar Y Ballester, Krishna Parsawar, M Minhaj Siddiqui, Jianjun Gao, Adriana Langer Gramer, Roni J Bollag, Martha K Terris, Yair Lotan, Chad J Creighton, Seth P Lerner, Arun Sreekumar, Benny Abraham Kaipparettu, Nagireddy Putluri.

  Bladder cancer (BLCA) mortality is higher in African American (AA) patients compared with European American (EA) patients, but the molecular mechanism underlying race-specific differences are unknown. To address this gap, we conducted comprehensive RNA-Seq, proteomics, and metabolomics analysis of BLCA tumors from AA and EA. Our findings reveal a distinct metabolic phenotype in AA BLCA characterized by elevated mitochondrial oxidative phosphorylation (OXPHOS), particularly through the activation of complex I. The results provide insight into the complex I activation-driven higher OXPHOS activity resulting in glutamine-mediated metabolic rewiring and increased disease progression, which was also confirmed by [U]13C-glutamine tracing. Mechanistic studies further demonstrate that knockdown of NDUFB8, one of the components of complex I in AA BLCA cells, resulted in reduced basal respiration, ATP production, GLS1 expression, and proliferation. Moreover, preclinical studies demonstrate the therapeutic potential of targeting complex I, as evidenced by decreased tumor growth in NDUFB8-depleted AA BLCA tumors. Additionally, genetic and pharmacological inhibition of GLS1 attenuated mitochondrial respiration rates and tumor growth potential in AA BLCA. Taken together, these findings provide insight into BLCA disparity for targeting GLS1-Complex I for future therapy.

Keywords:  Cancer; Metabolism; Mitochondria; Oncology; Urology

DOI:  https://doi.org/10.1172/jci.insight.172336
Cancer Lett. 2024 Sep 11. pii: S0304-3835(24)00637-2. [Epub ahead of print] 217242

Rewired glutamate metabolism diminishes cytostatic action of L-asparaginase.

Katerina Hlozkova, Maryna Vasylkivska, Adam Boufersaoui, Bryan Marzullo, Matus Kolarik, Natividad Alquezar-Artieda, Mehak Shaikh, Fatemeh Alaei Faradonbeh, Marketa Zaliova, Martina Zwyrtkova, Violeta Bakardijeva-Mihaylova, Meritxell Alberich-Jorda, Jan Trka, Daniel A Tennant, Julia Starkova.

Tumor cells often adapt to amino acid deprivation through metabolic rewiring, compensating for the loss with alternative amino acids/substrates. We have described such a scenario in leukemic cells treated with L-asparaginase (ASNase). Clinical effect of ASNase is based on nutrient stress achieved by its dual enzymatic action which leads to depletion of asparagine and glutamine and is accompanied with elevated aspartate and glutamate concentrations in serum of acute lymphoblastic leukemia patients. We showed that in these limited conditions glutamate uptake compensates for the loss of glutamine availability. Extracellular glutamate flux detection confirms its integration into the TCA cycle and its participation in nucleotide and glutathione synthesis. Importantly, it is glutamate-driven de novo synthesis of glutathione which is the essential metabolic pathway necessary for glutamate's pro-survival effect. In vivo findings support this effect by showing that inhibition of glutamate transporters enhances the therapeutic effect of ASNase. In summary, ASNase induces elevated extracellular glutamate levels under nutrient stress, which leads to a rewiring of intracellular glutamate metabolism and has a negative impact on ASNase treatment.

DOI: https://doi.org/10.1016/j.canlet.2024.217242
Cancers (Basel). 2024 Aug 30. pii: 3028. [Epub ahead of print]16(17):

ASCT2 Regulates Fatty Acid Metabolism to Trigger Glutamine Addiction in Basal-like Breast Cancer.

Jia Wang, Qian Zhang, Huaizi Fu, Yi Han, Xue Li, Qianlin Zou, Shengtao Yuan, Li Sun.

  As a crucial amino acid, glutamine can provide the nitrogen and carbon sources needed to support cancer cell proliferation, invasion, and metastasis. Interestingly, different types of breast cancer have different dependences on glutamine. This research shows that basal-like breast cancer depends on glutamine, while the other types of breast cancer may be more dependent on glucose. Glutamine transporter ASCT2 is highly expressed in various cancers and significantly promotes the growth of breast cancer. However, the key regulatory mechanism of ASCT2 in promoting basal-like breast cancer progression remains unclear. Our research demonstrates the significant change in fatty acid levels caused by ASCT2, which may be a key factor in glutamine sensitivity. This phenomenon results from the mutual activation between ASCT2-mediated glutamine transport and lipid metabolism via the nuclear receptor PPARα. ASCT2 cooperatively promoted PPARα expression, leading to the upregulation of lipid metabolism. Moreover, we also found that C118P could inhibit lipid metabolism by targeting ASCT2. More importantly, this research identifies a potential avenue of evidence for the prevention and early intervention of basal-like breast cancer by blocking the glutamine-lipid feedback loop.

Keywords:  ASCT2; basal-like breast cancer; glutamine; lipid metabolism

DOI:  https://doi.org/10.3390/cancers16173028
J Cell Physiol. 2024 Sep 08. e31417

Cancer knocks you out by fasting: Cachexia as a consequence of metabolic alterations in cancer.

Salvatore Cortellino, Margherita D'Angelo, Massimiliano Quintiliani, Antonio Giordano.

  Neoplastic transformation reprograms tumor and surrounding host cell metabolism, increasing nutrient consumption and depletion in the tumor microenvironment. Tumors uptake nutrients from neighboring normal tissues or the bloodstream to meet energy and anabolic demands. Tumor-induced chronic inflammation, a high-energy process, also consumes nutrients to sustain its dysfunctional activities. These tumor-related metabolic and physiological changes, including chronic inflammation, negatively impact systemic metabolism and physiology. Furthermore, the adverse effects of antitumor therapy and tumor obstruction impair the endocrine, neural, and gastrointestinal systems, thereby confounding the systemic status of patients. These alterations result in decreased appetite, impaired nutrient absorption, inflammation, and shift from anabolic to catabolic metabolism. Consequently, cancer patients often suffer from malnutrition, which worsens prognosis and increases susceptibility to secondary adverse events. This review explores how neoplastic transformation affects tumor and microenvironment metabolism and inflammation, leading to poor prognosis, and discusses potential strategies and clinical interventions to improve patient outcomes.

Keywords:  cachexia; cancer metabolism; detary interventions; inflammation; malnutrition

DOI:  https://doi.org/10.1002/jcp.31417
Redox Biol. 2024 Sep 05. pii: S2213-2317(24)00313-6. [Epub ahead of print]76 103335

Oxidative stress promotes oral carcinogenesis via Thbs1-mediated M1-like tumor-associated macrophages polarization.

Wei Li, Qingwen Zeng, Bing Wang, Chao Lv, Haoan He, Xi Yang, Bin Cheng, Xiaoan Tao.

  Although oxidative stress is closely associated with tumor invasion and metastasis, its' exact role and mechanism in the initial stage of oral cancer remain ambiguous. Glutamine uptake mediated by alanine-serine-cysteine transporter 2 (ASCT2) participates in glutathione synthesis to resolve oxidative stress. Currently, we firstly found that ASCT2 deletion caused oxidative stress in oral mucosa and promoted oral carcinogenesis induced by 4-Nitroquinoline-1-oxide (4-NQO) using transgenic mice of ASCT2 knockout in oral epithelium. Subsequently, we identified an upregulated gene Thbs1 linked to macrophage infiltration by mRNA sequencing and immunohistochemistry. Importantly, multiplex immunohistochemistry showed M1-like tumor-associated macrophages (TAMs) were enriched in cancerous area. Mechanically, targeted ASCT2 effectively curbed glutamine uptake and caused intracellular reactive oxygen species (ROS) accumulation, which upregulated Thbs1 in oral keratinocytes and then activated p38, Akt and SAPK/JNK signaling to polarize M1-like TAMs via exosome-transferred pathway. Moreover, we demonstrated M1-like TAMs promoted malignant progression of oral squamous cell carcinoma (OSCC) both in vitro and in vivo by a DOK transformed cell line induced by 4-NQO. All these results establish that oxidative stress triggered by ASCT2 deletion promotes oral carcinogenesis through Thbs1-mediated M1 polarization, and indicate that restore redox homeostasis is a new approach to prevent malignant progression of oral potentially malignant disorders.

Keywords:  ASCT2; Macrophages; Oral carcinogenesis; ROS; Thbs1

DOI:  https://doi.org/10.1016/j.redox.2024.103335
EMBO Rep. 2024 Sep 13.

Glutaminolysis provides nucleotides and amino acids to regulate osteoclast differentiation in mice.

Guoli Hu, Yilin Yu, Yinshi Ren, Robert J Tower, Guo-Fang Zhang, Courtney M Karner.

  Osteoclasts are bone resorbing cells that are essential to maintain skeletal integrity and function. While many of the growth factors and molecular signals that govern osteoclastogenesis are well studied, how the metabolome changes during osteoclastogenesis is unknown. Using a multifaceted approach, we identified a metabolomic signature of osteoclast differentiation consisting of increased amino acid and nucleotide metabolism. Maintenance of the osteoclast metabolic signature is governed by elevated glutaminolysis. Mechanistically, glutaminolysis provides amino acids and nucleotides which are essential for osteoclast differentiation and bone resorption in vitro. Genetic experiments in mice found that glutaminolysis is essential for osteoclastogenesis and bone resorption in vivo. Highlighting the therapeutic implications of these findings, inhibiting glutaminolysis using CB-839 prevented ovariectomy induced bone loss in mice. Collectively, our data provide strong genetic and pharmacological evidence that glutaminolysis is essential to regulate osteoclast metabolism, promote osteoclastogenesis and modulate bone resorption in mice.

Keywords:  Amino Acids; Glutaminolysis; Nucleotides; Osteoclast; Osteoporosis

DOI:  https://doi.org/10.1038/s44319-024-00255-x
bioRxiv. 2024 Aug 27. pii: 2024.08.26.609422. [Epub ahead of print]

IRF5 mediates adaptive immunity via altered glutamine metabolism, mTORC1 signaling and post-transcriptional regulation following T cell receptor activation.

Zarina Brune, Ailing Lu, Matthew Moss, Leianna Brune, Amanda Huang, Bharati Matta, Betsy J Barnes.

Although dynamic alterations in transcriptional, translational, and metabolic programs have been described in T cells, the factors and pathways guiding these molecular shifts are poorly understood, with recent studies revealing a disassociation between transcriptional responses and protein expression following T cell receptor (TCR) stimulation. Previous studies identified interferon regulatory factor 5 (IRF5) in the transcriptional regulation of cytokines, chemotactic molecules and T effector transcription factors following TCR signaling. In this study, we identified T cell intrinsic IRF5 regulation of mTORC1 activity as a key modulator of CD40L protein expression. We further demonstrated a global shift in T cell metabolism, with alterations in glutamine metabolism accompanied by shifts in T cell populations at the single cell level due to loss of Irf5. T cell conditional Irf5 knockout mice in a murine model of experimental autoimmune encephalomyelitis (EAE) demonstrated protection from clinical disease with conserved defects in mTORC1 activity and glutamine regulation. Together, these findings expand our mechanistic understanding of IRF5 as an intrinsic regulator of T effector function(s) and support the therapeutic targeting of IRF5 in multiple sclerosis.

DOI: https://doi.org/10.1101/2024.08.26.609422
J Colloid Interface Sci. 2024 Sep 06. pii: S0021-9797(24)02022-8. [Epub ahead of print]678(Pt B): 866-877

V9302-loaded copper-polyphenol hydrogel for enhancing the anti-tumor effect of disulfiram.

Zhongquan Sun, Shenyu Wei, Quanshi Guo, Hanxiang Ouyang, Zhengwei Mao, Weilin Wang, Zongrui Tong, Yuan Ding.

  Disulfiram (DSF) is a safe drug with negligible toxicity and Cu-dependent anti-tumor efficacy. However, the accumulation and combination of DSF and Cu in non-tumor tissues leads to systemic toxicity owing to the formation of highly poisonous diethyldithiocarbamate (CuET). In addition, CuET-mediated tumor-killing reactive oxygen species may be weakened by intra-tumoral glutathione (GSH). Herein, a synergistic treatment was developed that utilized the oral delivery of DSF and an injectable polyphenol-copper (PA-Cu) hydrogel loaded with the glutamine uptake inhibitor 2-amino-4-bis(phenoxymethyl)aminobutane (V9302). The injectable hydrogels were synthesized by the Schiff base reaction of hydroxypropyl chitosan (HPCS) with a PA-Cu reversible cross-linking agent. Because of the dynamic coordination between PA and Cu, the PA-Cu/HPCS hydrogel gradually releases Cu2+, forming CuET with DSF. The released V9302 inhibits glutamine uptake, thereby suppressing GSH synthesis and enhancing the therapeutic efficacy of the in situ formed CuET. The synergistic effect of PA-Cu/HPCS/V9302 and DSF in eliminating intracellular GSH and killing tumor cells was validated by in vitro cell experiments. Animal experiments further confirmed that PA-Cu/HPCS/V9302 and DSF have an inhibitory effect on tumor growth while maintaining the biosafety of main organs.

Keywords:  Disulfiram; Glutathione depletion; Hydrogels; Local therapy

DOI:  https://doi.org/10.1016/j.jcis.2024.08.240
BMC Pulm Med. 2024 Sep 13. 24(1): 451

Causal relationship between circulating glutamine levels and idiopathic pulmonary fibrosis: a two-sample mendelian randomization study.

Tao Xu, Chengyu Liu, Xuecong Ning, Zhiguo Gao, Aimin Li, Shengyun Wang, Lina Leng, Pinpin Kong, Pengshuai Liu, Shusen Zhang, Ping Zhang.

   BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive and debilitating respiratory disease with a median survival of less than 5 years. In recent years, glutamine has been reported to be involved in the regulation of collagen deposition and cell proliferation in fibroblasts, thereby influencing the progression of IPF. However, the relationships between glutamine and the incidence, progression, and treatment response of IPF remain unclear. Our study aimed to investigate the relationship between circulating glutamine levels and IPF, as well as its potential as a therapeutic target.
METHODS: We performed a comprehensive Mendelian Randomization (MR) analysis using the most recent genome-wide association study summary-level data. A total of 32 single nucleotide polymorphisms significantly correlated to glutamine levels were identified as instrumental variables. Eight MR analysis methods, including inverse variance weighted, MR-Egger, weighted median, weighted mode, constrained maximum likelihood, contamination mixture, robust adjusted profile score, and debiased inverse-variance weighted method, were used to assess the relationship between glutamine levels with IPF.
RESULTS: The inverse variance weighted analysis revealed a significant inverse correlation between glutamine levels and IPF risk (Odds Ratio = 0.750; 95% Confidence Interval : 0.592-0.951; P = 0.017). Sensitivity analyses, including MR-Egger regression and MR-PRESSO global test, confirmed the robustness of our findings, with no evidence of horizontal pleiotropy or heterogeneity.
CONCLUSION: Our study provides novel evidence for a causal relationship between lower circulating glutamine levels and increased risk of IPF. This finding may contribute to the early identification of high-risk individuals for IPF, disease monitoring, and development of targeted therapeutic strategies.

Keywords:  Causal relationship; GWAS; Glutamine; Idiopathic pulmonary fibrosis; Mendelian randomization

DOI:  https://doi.org/10.1186/s12890-024-03275-4
J Biol Chem. 2024 Sep 09. pii: S0021-9258(24)02254-3. [Epub ahead of print] 107753

Cortisol affects macrophage polarization by inducing miR-143/145 cluster to reprogram glucose metabolism and by promoting TCA cycle anaplerosis.

Amod Sharma, Kunwar Somesh Vikramdeo, Sarabjeet Kour Sudan, Shashi Anand, Sachin Kumar Deshmukh, Ajay Pratap Singh, Seema Singh.

  Chronic stress can have adverse consequences on human health by disrupting the hormonal balance in our body. Earlier, we observed elevated levels of cortisol, a primary stress hormone, and some exosomal microRNAs in the serum of breast cancer patients. Here, we investigated the role of cortisol in microRNA induction and its functional consequences. We found that cortisol induced the expression of miR-143/145 cluster in human monocyte (THP1 and U937)-derived macrophages but not in breast cancer cells. In silico analysis identified glucocorticoid-response element in the upstream CARMN promoter utilized by the miR-143/145 cluster. Enhanced binding of glucocorticoid-receptor (GR) upon cortisol exposure and its regulatory significance was confirmed by chromatin-immunoprecipitation and promoter-reporter assays. Further, cortisol inhibited IFNγ-induced M1 polarization and promoted M2 polarization, and these effects were suppressed by miR-143-3p and miR-145-5p inhibitors pretreatment. Cortisol-treated macrophages exhibited increased oxygen-consumption rate (OCR) to extracellular-acidification rate (ECAR) ratio, and this change was neutralized by functional inhibition of miR-143-3p and miR-145-5p. HK2 and ADPGK were confirmed as the direct targets of miR-143-3p and miR-145-5p, respectively. Interestingly, silencing of HK2 and ADPGK inhibited IFNγ-induced M1 polarization, but failed to induce M2 polarization, since it suppressed both ECAR and OCR, while OCR was largely sustained in cortisol-treated M2-polarized macrophages. We found that cortisol treatment sustained OCR by enhancing fatty acid and glutamine metabolism through upregulation of CPT2 and GLS, respectively, to support M2 polarization. Thus, our findings unfold a novel mechanism of immune suppression by cortisol and open avenues for preventive and therapeutic interventions.

Keywords:  Cortisol; Macrophage; Polarization; miR-145-5p; miRNA-143-3p

DOI:  https://doi.org/10.1016/j.jbc.2024.107753
Cells. 2024 Sep 02. pii: 1474. [Epub ahead of print]13(17):

Unraveling the Mystery of Energy-Sensing Enzymes and Signaling Pathways in Tumorigenesis and Their Potential as Therapeutic Targets for Cancer.

Zeenat Mirza, Sajjad Karim.

  Cancer research has advanced tremendously with the identification of causative genes, proteins, and signaling pathways. Numerous antitumor drugs have been designed and screened for cancer therapeutics; however, designing target-specific drugs for malignant cells with minimal side effects is challenging. Recently, energy-sensing- and homeostasis-associated molecules and signaling pathways playing a role in proliferation, apoptosis, autophagy, and angiogenesis have received increasing attention. Energy-metabolism-based studies have shown the contribution of energetics to cancer development, where tumor cells show increased glycolytic activity and decreased oxidative phosphorylation (the Warburg effect) in order to obtain the required additional energy for rapid division. The role of energy homeostasis in the survival of normal as well as malignant cells is critical; therefore, fuel intake and expenditure must be balanced within acceptable limits. Thus, energy-sensing enzymes detecting the disruption of glycolysis, AMP, ATP, or GTP levels are promising anticancer therapeutic targets. Here, we review the common energy mediators and energy sensors and their metabolic properties, mechanisms, and associated signaling pathways involved in carcinogenesis, and explore the possibility of identifying drugs for inhibiting the energy metabolism of tumor cells. Furthermore, to corroborate our hypothesis, we performed meta-analysis based on transcriptomic profiling to search for energy-associated biomarkers and canonical pathways.

Keywords:  Warburg effect; anticancer drug; cancer; energy-sensing enzymes; genes and signaling pathways

DOI:  https://doi.org/10.3390/cells13171474
Biochem Biophys Res Commun. 2024 Sep 05. pii: S0006-291X(24)01195-1. [Epub ahead of print]734 150659

Specific inhibitory effects of exogenous d-Aspartate on the proliferation of intestinal epithelial cells.

Yusuke Takizawa, Takahito Furuya, Masaya Uno, Ryuto Ohashi, Eiichi Mimura, Takuro Kurita, Takanori Nakajima.

  d-amino acids have been actively examined since improved analytical techniques revealed their presence in animal bodies. Although D-Asp was identified in mammals earlier than D-Ser, research on D-Asp has lagged behind that on D-Ser, mainly because the target protein of D-Asp remains unknown. To date, the only reported functions of D-Asp are its roles in reproduction and suggested neuromodulatory functions. Since d-amino acids are also present in food, it is important to clarify their effects on gastrointestinal epithelial cells, which are always contacted after ingestion. Therefore, the present study examined the effects of d-amino acids on gastrointestinal tract basal cells. The effects of 11 types of amino acids (Ala, Arg, Asn, Asp, Gln, Glu, Leu, Lys, Pro, Ser, and Val) on the proliferation of three types of gastrointestinal epithelial cells (HGC-27, IEC-6, and Caco-2) were assessed. Although the proliferation of HGC-27 and Caco-2 was not affected by any of the 11 types of L- and d-amino acids, D-Asp inhibited the proliferation of IEC-6, derived from small intestinal epithelial cells, in concentration- and exposure time-dependent manners. The present study also examined uptake transporters, metabolic enzymes, and insulin signaling pathways; however, the mechanisms underlying the inhibitory effects of D-Asp on the proliferation of IEC-6 were not elucidated. A more detailed understanding of these mechanisms may lead to the development of pharmaceuticals as main drugs or formulation materials. Further studies are warranted on the physiological effects of d-amino acids, including D-Asp.

Keywords:  Aspartate; Glutamine transporter; Intestinal epithelial cell; Proliferation suppression; d-amino acid

DOI:  https://doi.org/10.1016/j.bbrc.2024.150659
Hum Pathol. 2024 Sep 06. pii: S0046-8177(24)00164-3. [Epub ahead of print]153 105655

Glutamine synthetase staining patterns in cirrhosis.

Eric D Nguyen, Chien-Kuang Cornelia Ding, Sarah E Umetsu, Linda D Ferrell, Kwun Wah Wen.

  Advanced liver fibrosis can regress following the elimination of causative injuries. Glutamine synthetase (GS) immunohistochemical expression is normally in centrizonal perivenular hepatocytes but can be present in periportal hepatocytes in cases of regressed cirrhosis. This study identified periportal staining and investigated the spectrum of GS staining patterns seen in a range of cirrhotic livers with varying disease processes. The hematoxylin and eosin and GS-stained slides of 88 liver resection/explant specimens with advanced fibrosis cases by different causes were reviewed, and trichrome and orcein stains were used to classify cases as progressive, indeterminate, or regressive. Periportal GS staining was seen in 97% of regressive cases and 84% progressive or indeterminate cases. Liver resection specimens with periportal GS staining showed a variety of patterns, including predominantly perivenular, predominantly periseptal, and perinodular staining. The GS periseptal pattern is more common in regressed cirrhosis compared to progressive cases. The perinodular staining was seen in 16 cases resulting from various etiologies, including biliary atresia, steatotic liver disease, primary biliary cholangitis, and viral hepatitis, 75% of which demonstrated cholestasis. This study further subclassified GS staining patterns of "periportal" pattern in cirrhotic liver. Compared to orcein/trichrome staining, GS immunohistochemical staining is not as useful in distinguishing regressed cases from non-regressed cases.

Keywords:  Cirrhosis; Fibrosis; Glutamine synthetase; Progression; Regression

DOI:  https://doi.org/10.1016/j.humpath.2024.105655
EMBO Mol Med. 2024 Sep 13.

Multiomics reveals microbial metabolites as key actors in intestinal fibrosis in Crohn's disease.

Xuehua Li, Shixian Hu, Xiaodi Shen, Ruonan Zhang, Caiguang Liu, Lin Xiao, Jinjiang Lin, Li Huang, Weitao He, Xinyue Wang, Lili Huang, Qingzhu Zheng, Luyao Wu, Canhui Sun, Zhenpeng Peng, Minhu Chen, Ziping Li, Rui Feng, Yijun Zhu, Yangdi Wang, Zhoulei Li, Ren Mao, Shi-Ting Feng.

  Intestinal fibrosis is the primary cause of disability in patients with Crohn's disease (CD), yet effective therapeutic strategies are currently lacking. Here, we report a multiomics analysis of gut microbiota and fecal/blood metabolites of 278 CD patients and 28 healthy controls, identifying characteristic alterations in gut microbiota (e.g., Lachnospiraceae, Ruminococcaceae, Muribaculaceae, Saccharimonadales) and metabolites (e.g., L-aspartic acid, glutamine, ethylmethylacetic acid) in moderate-severe intestinal fibrosis. By integrating multiomics data with magnetic resonance enterography features, putative links between microbial metabolites and intestinal fibrosis-associated morphological alterations were established. These potential associations were mediated by specific combinations of amino acids (e.g., L-aspartic acid), primary bile acids, and glutamine. Finally, we provided causal evidence that L-aspartic acid aggravated intestinal fibrosis both in vitro and in vivo. Overall, we offer a biologically plausible explanation for the hypothesis that gut microbiota and its metabolites promote intestinal fibrosis in CD while also identifying potential targets for therapeutic trials.

Keywords:  Crohn’s Disease; Fibrosis; Gut Microbiota; Magnetic Resonance Enterography; Metabolites

DOI:  https://doi.org/10.1038/s44321-024-00129-8
Colloids Surf B Biointerfaces. 2024 Sep 03. pii: S0927-7765(24)00455-7. [Epub ahead of print]245 114196

Cu0-based nanoparticles boost anti-tumor efficacy via synergy of cuproptosis and ferroptosis enhanced by cuproptosis-induced glutathione synthesis disorder.

Yichen Wan, Junge Chen, Jiaxuan Li, Zelong Chen, Yi Wang, Jiahui Li, Zhichao Pei, Yuxin Pei.

  Apoptotic resistance of tumor often leads to poor efficacy from mono-therapy based on apoptosis. Cuproptosis, a new type of non-apoptotic cell death related to mitochondrial dysfunction, can alter metabolism and enhance ferroptosis, providing a promising strategy for effective synergistic cancer treatment. In this work, Cu0-based nanoparticles (denoted as HA-ZCu) were successfully developed to improve anti-tumor efficacy by combining cuproptosis with enhanced ferroptosis, which was achieved by cuproptosis-induced glutathione synthesis disorder. In vitro studies revealed that HA-ZCu effectively induced cuproptosis and ferroptosis in HepG2 cells. Moreover, HA-ZCu induced mitochondrial dysfunction and decreased intracellular adenosine triphosphate (ATP), glutamate, and glutathione, demonstrating the effective synergy. In vivo studies further approved the synergistic therapeutic efficacy of HA-ZCu, where the inhibition rate of tumor growth reached 83.2 %. This work represents the first example of enhanced anti-tumor efficacy via cuproptosis and ferroptosis synergy through cuproptosis-induced glutathione synthesis disorder.

Keywords:  Cuproptosis; Ferroptosis; Glutathione synthesis; Synergistic therapy; Zero-valent copper

DOI:  https://doi.org/10.1016/j.colsurfb.2024.114196
Pharmacol Rep. 2024 Sep 11.

Disrupted glutamate homeostasis as a target for glioma therapy.

Mikołaj Biegański, Monika Szeliga.

  Glutamate is the major excitatory neurotransmitter in the central nervous system (CNS). Gliomas, malignant brain tumors with a dismal prognosis, alter glutamate homeostasis in the brain, which is advantageous for their growth, survival, and invasion. Alterations in glutamate homeostasis result from its excessive production and release to the extracellular space. High glutamate concentration in the tumor microenvironment destroys healthy tissue surrounding the tumor, thus providing space for glioma cells to expand. Moreover, it confers neuron hyperexcitability, leading to epilepsy, a common symptom in glioma patients. This mini-review briefly describes the biochemistry of glutamate production and transport in gliomas as well as the activation of glutamate receptors. It also summarizes the current pre-clinical and clinical studies identifying pharmacotherapeutics targeting glutamate transporters and receptors emerging as potential therapeutic strategies for glioma.

Keywords:  Glioblastoma; Glutamate; Glutamate receptors; Glutamate transport; Neurotoxicity

DOI:  https://doi.org/10.1007/s43440-024-00644-y