bims-glucam 2022-03-13 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2022–03–13
eightteen papers selected by
Sreeparna Banerjee, Middle East Technical University

Targeting glutamine utilization to block metabolic adaptation of tumor cells under the stress of carboxyamidotriazole-induced nutrients unavailability.
RUNX3-mediated circDYRK1A inhibits glutamine metabolism in gastric cancer by up-regulating microRNA-889-3p-dependent FBXO4.
Glucose and glutamine metabolism-related protein expression in breast ductal carcinoma in situ.
Comprehensive Metabolic Profiling of MYC-Amplified Medulloblastoma Tumors Reveals Key Dependencies on Amino Acid, Tricarboxylic Acid and Hexosamine Pathways.
Metabolic Regulation: A Potential Strategy for Rescuing Stem Cell Senescence.
Tumor-derived exosomes co-delivering aggregation-induced emission luminogens and proton pump inhibitors for tumor glutamine starvation therapy and enhanced type-I photodynamic therapy.
Metabolic dysregulation and emerging therapeutical targets for hepatocellular carcinoma.
Mammalian HEMK1 methylates glutamine residue of the GGQ motif of mitochondrial release factors.
The metabolomic landscape plays a critical role in glioma oncogenesis.
A non-canonical tricarboxylic acid cycle underlies cellular identity.
Metabolic tricks of cancer cells.
Diaminobutoxy-substituted Isoflavonoid (DBI-1) Enhances the Therapeutic Efficacy of GLUT1 inhibitor BAY-876 by Modulating Metabolic Pathways in Colon Cancer Cells.
Targeting metabolism to overcome cancer drug resistance: A promising therapeutic strategy for diffuse large B cell lymphoma.
Brucein D augments the chemosensitivity of gemcitabine in pancreatic cancer via inhibiting the Nrf2 pathway.
Comprehensive analysis of metabolic isozyme targets in cancer.
Impact of Parenteral Glutamine Supplement on Oncologic Outcomes in Patients with Nasopharyngeal Cancer Treated with Concurrent Chemoradiotherapy.
Cancer progression as a learning process.
Comprehensive Characterization of Metabolism-Associated Subtypes of Renal Cell Carcinoma to Aid Clinical Therapy.

Acta Pharm Sin B. 2022 Feb;12(2): 759-773

Targeting glutamine utilization to block metabolic adaptation of tumor cells under the stress of carboxyamidotriazole-induced nutrients unavailability.

Jing Shi, Rui Ju, Hongting Gao, Yuqing Huang, Lei Guo, Dechang Zhang.

  Tumor cells have unique metabolic programming that is biologically distinct from that of corresponding normal cells. Resetting tumor metabolic programming is a promising strategy to ameliorate drug resistance and improve the tumor microenvironment. Here, we show that carboxyamidotriazole (CAI), an anticancer drug, can function as a metabolic modulator that decreases glucose and lipid metabolism and increases the dependency of colon cancer cells on glutamine metabolism. CAI suppressed glucose and lipid metabolism utilization, causing inhibition of mitochondrial respiratory chain complex I, thus producing reactive oxygen species (ROS). In parallel, activation of the aryl hydrocarbon receptor (AhR) increased glutamine uptake via the transporter SLC1A5, which could activate the ROS-scavenging enzyme glutathione peroxidase. As a result, combined use of inhibitors of GLS/GDH1, CAI could effectively restrict colorectal cancer (CRC) energy metabolism. These data illuminate a new antitumor mechanism of CAI, suggesting a new strategy for CRC metabolic reprogramming treatment.

Keywords:  2-NBDG, glucalogue 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose; ATP, adenosine triphosphate; AhR; AhR, aryl hydrocarbon receptor; CAI; CAI, carboxyamidotriazole; CHIP, chromatin immunoprecipitation; CRC, colorectal cancer; Colorectal cancer metabolism; DMF, 3′,4′-dimethoxyflavone; DNA, deoxyribonucleic acid; ECAR, extracellular acidification rate; FACS, flow cytometry; GDH1, glutamate dehydrogenase 1; GLS, glutaminase; GPx, glutathione peroxidase; GSH, glutathione; GSSG, oxidized glutathione; Glutamine metabolism; Glutaminolysis; Kyn, kynurenine; MT, mito-TEMPO; Metabolic reprogramming; Mito-Q, mitoquinone mesylate; Mitochondrial oxidative stress; OCR, oxygen consumption rate; Redox homeostasis; TCA, tricarboxylic acid; α-KG, α-ketoglutarate

DOI:  https://doi.org/10.1016/j.apsb.2021.07.008
J Transl Med. 2022 Mar 10. 20(1): 120

RUNX3-mediated circDYRK1A inhibits glutamine metabolism in gastric cancer by up-regulating microRNA-889-3p-dependent FBXO4.

Haofeng Liu, Qiu Xue, Hongzhou Cai, Xiaohui Jiang, Guangxin Cao, Tie Chen, Yuan Chen, Ding Wang.

   BACKGROUND: Targeting glutamine metabolism is previously indicated as a potential and attractive strategy for gastric cancer (GC) therapy. However, the underlying mechanisms responsible for the modification of glutamine metabolism in GC cells have not been fully elucidated. Accordingly, the current study sought to investigate the physiological mechanisms of RUNX3-mediated circDYRK1A in glutamine metabolism of GC.
METHODS: Firstly, GC tissues and adjacent normal tissues were obtained from 50 GC patients to determine circDYRK1A expression in GC tissues. Next, the binding affinity among RUNX3, circDYRK1A, miR-889-3p, and FBXO4 was detected to clarify the mechanistic basis. Moreover, GC cells were subjected to ectopic expression and knockdown manipulations of circDYRK1A, miR-889-3p, and/or FBXO4 to assay GC cell malignant phenotypes, levels of glutamine, glutamic acid, and α-KG in cell supernatant and glutamine metabolism-related proteins (GLS and GDH). Finally, nude mice were xenografted with GC cells to explore the in vivo effects of circDYRK1A on the tumorigenicity and apoptosis.
RESULTS: circDYRK1A was found to be poorly expressed in GC tissues. RUNX3 was validated to bind to the circDYRK1A promoter, and circDYRK1A functioned as a miR-889-3p sponge to up-regulate FBXO4 expression. Moreover, RUNX3-upregulated circDYRK1A reduced levels of glutamine, glutamic acid, and α-KG, and protein levels of GLS and GDH, and further diminished malignant phenotypes in vitro. Furthermore, in vivo experimentation substantiated that circDYRK1A inhibited the tumorigenicity and augmented the apoptosis in GC.
CONCLUSION: In conclusion, these findings highlighted the significance and mechanism of RUNX3-mediated circDYRK1A in suppressing glutamine metabolism in GC via the miR-889-3p/FBXO4 axis.

Keywords:  CircDYRK1A; FBXO4; Gastric cancer; Glutamine metabolism; MicroRNA-889-3p; RUNX3; Sponge

DOI:  https://doi.org/10.1186/s12967-022-03286-x
Neoplasma. 2022 Mar 10. pii: 220103N3. [Epub ahead of print]

Glucose and glutamine metabolism-related protein expression in breast ductal carcinoma in situ.

Hyang Joo Ryu, Ja Seung Koo.

Glucose and glutamine metabolism is involved in important tumor mechanisms. Metabolism-related protein expression has been previously reported to predict tumor prognosis. We aimed to investigate glucose and glutamine metabolism-related protein expression and its implication in breast ductal carcinoma in situ (DCIS). A tissue microarray was prepared for 205 DCIS cases. Glucose and glutamine metabolism-related proteins were immunostained. Based on the results of estrogen receptor, progesterone receptor, human epidermal growth factor receptor (HER)-2, and Ki-67, DCIS was classified into the luminal type, HER-2 type, and triple-negative breast cancer (TNBC). DCIS stroma was classified into non-inflammatory and inflammatory types per stromal histology. DCIS (n = 205) were classified into luminal type (n = 112), HER-2 type (n = 81), and TNBC (n = 12). Hexokinase II (p = 0.044), GLS (p = 0.003), and SLC7A5 (p <0.001) expression rates were the highest in TNBC. Inflammatory type stroma showed higher SLC7A5 (p <0.001) and SLC7A11 (p=0.008) expression rates than non-inflammatory type stroma. In summary, DCIS demonstrated differential expression of metabolism-related proteins according to the molecular subtype and stromal features. TNBC showed the highest glucose and glutamine metabolism-related protein expression, and inflammatory type stroma showed higher glutamine metabolism-related protein expression than non-inflammatory type stroma.

DOI: https://doi.org/10.4149/neo_2022_220103N3
Cancers (Basel). 2022 Mar 03. pii: 1311. [Epub ahead of print]14(5):

Comprehensive Metabolic Profiling of MYC-Amplified Medulloblastoma Tumors Reveals Key Dependencies on Amino Acid, Tricarboxylic Acid and Hexosamine Pathways.

Khoa Pham, Allison R Hanaford, Brad A Poore, Micah J Maxwell, Heather Sweeney, Akhila Parthasarathy, Jesse Alt, Rana Rais, Barbara S Slusher, Charles G Eberhart, Eric H Raabe.

  Reprograming of cellular metabolism is a hallmark of cancer. Altering metabolism allows cancer cells to overcome unfavorable microenvironment conditions and to proliferate and invade. Medulloblastoma is the most common malignant brain tumor of children. Genomic amplification of MYC defines a subset of poor-prognosis medulloblastoma. We performed comprehensive metabolic studies of human MYC-amplified medulloblastoma by comparing the metabolic profiles of tumor cells in three different conditions-in vitro, in flank xenografts and in orthotopic xenografts in the cerebellum. Principal component analysis showed that the metabolic profiles of brain and flank high-MYC medulloblastoma tumors clustered closely together and separated away from normal brain and in vitro MYC-amplified cells. Compared to normal brain, MYC-amplified medulloblastoma orthotopic xenograft tumors showed upregulation of the TCA cycle as well as the synthesis of nucleotides, hexosamines, amino acids and glutathione. There was significantly higher glucose uptake and usage in orthotopic xenograft tumors compared to flank xenograft tumors and cells in culture. In orthotopic tumors, glucose was the main carbon source for the de novo synthesis of glutamate, glutamine and glutathione through the TCA cycle. In vivo, the glutaminase II pathway was the main pathway utilizing glutamine. Glutathione was the most abundant upregulated metabolite in orthotopic tumors compared to normal brain. Glutamine-derived glutathione was synthesized through the glutamine transaminase K (GTK) enzyme in vivo. In conclusion, high MYC medulloblastoma cells have different metabolic profiles in vitro compared to in vivo, and key vulnerabilities may be missed by not performing in vivo metabolic analyses.

Keywords:  Warburg effect; cancer metabolism; isotope labeling; mass spectrometry; pediatric brain tumor

DOI:  https://doi.org/10.3390/cancers14051311
Stem Cell Rev Rep. 2022 Mar 08.

Metabolic Regulation: A Potential Strategy for Rescuing Stem Cell Senescence.

Wenxin Zhang, Jiayu Li, Yuchi Duan, Yanlin Li, Yanan Sun, Hui Sun, Xiao Yu, Xingyu Gao, Chang Zhang, Haiying Zhang, Yingai Shi, Xu He.

  Stem cell senescence and exhaustion are closely related to organ failure and individual aging, which not only induces age-related diseases, but also hinders stem cell applications in regenerative medicine. Thus, it's imminent to find effective ways to delay and retrieve stem cell senescence. Metabolic abnormalities are one of the main characteristics of age-associated declines in stem cell function. Understanding the underlying mechanisms may reveal potential strategies for ameliorating age-associated phenotypes and treating age-related diseases. This review focuses on recent advances in the association between metabolism including glucose, lipid, glutamine and NAD+ metabolism and stem cell senescence, as well as the other properties like proliferation and differentiation. Layers of studies are summarized to demonstrate how metabolism varies in senescent stem cells and how metabolic reprogramming regulates stem cell senescence. Additionally, we mentioned some recent progress in therapeutic strategies to rejuvenate dysfunctional aged stem cells. Finally, a brief conclusion about the prospect of metabolic regulation as a potential strategy for rescuing stem cell senescence is displayed. Stem cell senescence is induced by the metabolic reprogramming. The metabolic alterations of glucose, lipid, glutamine and NAD+ can conversely facilitate or inhibit stem cell senescence. Glycolysis, OXPHOS and PPP are all attenuated. But gluconeogenesis alterations still remain unclear. In lipid metabolisms, both FAO and DNL are suppressed. As for the glutamine metabolism, stem cells' dependence on glutamine is enhanced. Last, NAD+ metabolism undergoes a down-regulated synthesis and up-regulated consumption. All these alterations can be potential targets for reversing stem cell senescence.

Keywords:  NAD+ metabolism; age-related diseases; glucose metabolism; glutamine metabolism; lipid metabolism; stem cell senescence

DOI:  https://doi.org/10.1007/s12015-022-10348-6
Biomaterials. 2022 Mar 05. pii: S0142-9612(22)00101-6. [Epub ahead of print]283 121462

Tumor-derived exosomes co-delivering aggregation-induced emission luminogens and proton pump inhibitors for tumor glutamine starvation therapy and enhanced type-I photodynamic therapy.

Daoming Zhu, Tianfu Zhang, Yang Li, Chunyu Huang, Meng Suo, Ligang Xia, Youhua Xu, Guoxin Li, Ben Zhong Tang.

  Although promising, the efficiency of aggregation-induced emission luminogens (AIEgens)-based photodynamic therapy (PDT) is limited by cellular glutathione (GSH). GSH is not a terminal reducing agent but it can be oxidized and subsequently reduced to its original state by reductases to further participate in antioxidant activity. It is therefore imperative to control GSH for effectively inducing oxidation within tumor cells. Recent studies showed that tumor cell metabolism depends mainly on glutamine, which is also the nitrogen and ATP source for GSH synthesis. Therefore, glutamine-based starvation therapy may be effective in enhancing photodynamic therapy. In this work, tumor-derived exosomes were developed for co-delivering AIEgens and proton pump inhibitors (PPI) for tumor combination therapy. Tumor-derived exosomes could specifically deliver drugs to the tumor sites, where PPI inhibited cell glutamine metabolism, suppressed tumor cell GSH and ATP production, and improved the effect of type-I PDT from AIEgens. When used in the treatment of MGC803 gastric cancer subcutaneous model, our system shows a high tumor growth inhibition rate, and even promoting tumor immunogenic death. This is the first work which combine inhibition of glutamine metabolism with PDT, and it has the potential to be applied for future designs of new tumor metabolic therapies and photodynamic systems.

Keywords:  Aggregation-induced emission luminogens; Enhanced type-I photodynamic therapy; Glutamine starvation therapy; Proton pump inhibitors; Tumor-derived exosomes

DOI:  https://doi.org/10.1016/j.biomaterials.2022.121462
Acta Pharm Sin B. 2022 Feb;12(2): 558-580

Metabolic dysregulation and emerging therapeutical targets for hepatocellular carcinoma.

Danyu Du, Chan Liu, Mengyao Qin, Xiao Zhang, Tao Xi, Shengtao Yuan, Haiping Hao, Jing Xiong.

  Hepatocellular carcinoma (HCC) is an aggressive human cancer with increasing incidence worldwide. Multiple efforts have been made to explore pharmaceutical therapies to treat HCC, such as targeted tyrosine kinase inhibitors, immune based therapies and combination of chemotherapy. However, limitations exist in current strategies including chemoresistance for instance. Tumor initiation and progression is driven by reprogramming of metabolism, in particular during HCC development. Recently, metabolic associated fatty liver disease (MAFLD), a reappraisal of new nomenclature for non-alcoholic fatty liver disease (NAFLD), indicates growing appreciation of metabolism in the pathogenesis of liver disease, including HCC, thereby suggesting new strategies by targeting abnormal metabolism for HCC treatment. In this review, we introduce directions by highlighting the metabolic targets in glucose, fatty acid, amino acid and glutamine metabolism, which are suitable for HCC pharmaceutical intervention. We also summarize and discuss current pharmaceutical agents and studies targeting deregulated metabolism during HCC treatment. Furthermore, opportunities and challenges in the discovery and development of HCC therapy targeting metabolism are discussed.

Keywords:  1,3-BPG, 1,3-bisphosphoglycerate; 2-DG, 2-deoxy-d-glucose; 3-BrPA, 3-bromopyruvic acid; ACC, acetyl-CoA carboxylase; ACLY, adenosine triphosphate (ATP) citrate lyase; ACS, acyl-CoA synthease; AKT, protein kinase B; AML, acute myeloblastic leukemia; AMPK, adenosine mono-phosphate-activated protein kinase; ASS1, argininosuccinate synthase 1; ATGL, adipose triacylglycerol lipase; CANA, canagliflozin; CPT, carnitine palmitoyl-transferase; CYP4, cytochrome P450s (CYPs) 4 family; Cancer therapy; DNL, de novo lipogenesis; EMT, epithelial-to-mesenchymal transition; ER, endoplasmic reticulum; ERK, extracellular-signal regulated kinase; FABP1, fatty acid binding protein 1; FASN, fatty acid synthase; FBP1, fructose-1,6-bisphosphatase 1; FFA, free fatty acid; Fatty acid β-oxidation; G6PD, glucose-6-phosphate dehydrogenase; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GLS1, renal-type glutaminase; GLS2, liver-type glutaminase; GLUT1, glucose transporter 1; GOT1, glutamate oxaloacetate transaminase 1; Glutamine metabolism; Glycolysis; HCC, hepatocellular carcinoma; HIF-1α, hypoxia-inducible factor-1 alpha; HK, hexokinase; HMGCR, 3-hydroxy-3-methylglutaryl-CoA reductase; HSCs, hepatic stellate cells; Hepatocellular carcinoma; IDH2, isocitrate dehydrogenase 2; LCAD, long-chain acyl-CoA dehydrogenase; LDH, lactate dehydrogenase; LPL, lipid lipase; LXR, liver X receptor; MAFLD, metabolic associated fatty liver disease; MAGL, monoacyglycerol lipase; MCAD, medium-chain acyl-CoA dehydrogenase; MEs, malic enzymes; MMP9, matrix metallopeptidase 9; Metabolic dysregulation; NADPH, nicotinamide adenine nucleotide phosphate; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; OTC, ornithine transcarbamylase; PCK1, phosphoenolpyruvate carboxykinase 1; PFK1, phosphofructokinase 1; PGAM1, phosphoglycerate mutase 1; PGK1, phosphoglycerate kinase 1; PI3K, phosphoinositide 3-kinase; PKM2, pyruvate kinase M2; PPARα, peroxisome proliferator-activated receptor alpha; PPP, pentose phosphate pathway; Pentose phosphate pathway; ROS, reactive oxygen species; SCD1, stearoyl-CoA-desaturase 1; SGLT2, sodium-glucose cotransporter 2; SLC1A5/ASCT2, solute carrier family 1 member 5/alanine serine cysteine preferring transporter 2; SLC7A5/LAT1, solute carrier family 7 member 5/L-type amino acid transporter 1; SREBP1, sterol regulatory element-binding protein 1; TAGs, triacylglycerols; TCA cycle, tricarboxylic acid cycle; TKIs, tyrosine kinase inhibitors; TKT, transketolase; Tricarboxylic acid cycle; VEGFR, vascular endothelial growth factor receptor; WD-fed MC4R-KO, Western diet (WD)-fed melanocortin 4 receptor-deficient (MC4R-KO); WNT, wingless-type MMTV integration site family; mIDH, mutant IDH; mTOR, mammalian target of rapamycin

DOI:  https://doi.org/10.1016/j.apsb.2021.09.019
Sci Rep. 2022 Mar 08. 12(1): 4104

Mammalian HEMK1 methylates glutamine residue of the GGQ motif of mitochondrial release factors.

Qi Fang, Yusuke Kimura, Tadahiro Shimazu, Takehiro Suzuki, Ayumi Yamada, Naoshi Dohmae, Shintaro Iwasaki, Yoichi Shinkai.

Despite limited reports on glutamine methylation, methylated glutamine is found to be highly conserved in a "GGQ" motif in both prokaryotes and eukaryotes. In bacteria, glutamine methylation of peptide chain release factors 1/2 (RF1/2) by the enzyme PrmC is essential for translational termination and transcript recycling. Two PrmC homologs, HEMK1 and HEMK2, are found in mammals. In contrast to those of HEMK2, the biochemical properties and biological significance of HEMK1 remain largely unknown. In this study, we demonstrated that HEMK1 is an active methyltransferase for the glutamine residue of the GGQ motif of all four putative mitochondrial release factors (mtRFs)-MTRF1, MTRF1L, MRPL58, and MTRFR. In HEMK1-deficient HeLa cells, GGQ motif glutamine methylation was absent in all the mtRFs. We examined cell growth and mitochondrial properties, but disruption of the HEMK1 gene had no considerable impact on the overall cell growth, mtDNA copy number, mitochondrial membrane potential, and mitochondrial protein synthesis under regular culture condition with glucose as a carbon source. Furthermore, cell growth potential of HEMK1 KO cells was still maintained in the respiratory condition with galactose medium. Our results suggest that HEMK1 mediates the GGQ methylation of all four mtRFs in human cells; however, this specific modification seems mostly dispensable in cell growth and mitochondrial protein homeostasis at least for HeLa cells under fermentative culture condition.

DOI: https://doi.org/10.1038/s41598-022-08061-y
Cancer Sci. 2022 Mar 10.

The metabolomic landscape plays a critical role in glioma oncogenesis.

Kenta Masui, Webster K Cavenee, Paul S Mischel, Noriyuki Shibata.

  Cancer cells depend on metabolic reprogramming for survival, undergoing profound shifts in nutrient-sensing, nutrient uptake and flux through anabolic pathways, in order to drive nucleotide, lipid, and protein synthesis and provide key intermediates needed for those pathways. Although metabolic enzymes themselves can be mutated, including to generate oncometabolites, this is a relatively rare event in cancer. Usually, gene amplification, overexpression, and/or downstream signal transduction upregulate rate-limiting metabolic enzymes and limit feedback loops, to drive persistent tumor growth. Recent molecular genetic advances revealed discrete links between oncogenotypes and the resultant metabolic phenotypes. However, more comprehensive approaches are needed to unravel the dynamic spatio-temporal regulatory map of enzymes and metabolites that enable cancer cells to adapt to their microenvironment to maximize tumor growth. Proteomic and metabolomic analyses are powerful tools for analyzing a repertoire of metabolic enzymes as well as intermediary metabolites, and in conjunction with other omic approaches could provide critical information in this regard. Here, we provide an overview of cancer metabolism, especially from an "omics" perspective and with a particular focus on the genomically well-characterized malignant tumor, glioblastoma. We further discuss how metabolomics could be leveraged to improve the management of patients, by linking cancer cell genotype, epigenotype and phenotype through metabolic reprogramming.

Keywords:  OMICS; epigenetics; glioblastoma; mTOR complex; metabolome

DOI:  https://doi.org/10.1111/cas.15325
Nature. 2022 Mar 09.

A non-canonical tricarboxylic acid cycle underlies cellular identity.

Paige K Arnold, Benjamin T Jackson, Katrina I Paras, Julia S Brunner, Madeleine L Hart, Oliver J Newsom, Sydney P Alibeckoff, Jennifer Endress, Esther Drill, Lucas B Sullivan, Lydia W S Finley.

The tricarboxylic acid (TCA) cycle is a central hub of cellular metabolism, oxidizing nutrients to generate reducing equivalents for energy production and critical metabolites for biosynthetic reactions. Despite the importance of the products of the TCA cycle for cell viability and proliferation, mammalian cells display diversity in TCA-cycle activity1,2. How this diversity is achieved, and whether it is critical for establishing cell fate, remains poorly understood. Here we identify a non-canonical TCA cycle that is required for changes in cell state. Genetic co-essentiality mapping revealed a cluster of genes that is sufficient to compose a biochemical alternative to the canonical TCA cycle, wherein mitochondrially derived citrate exported to the cytoplasm is metabolized by ATP citrate lyase, ultimately regenerating mitochondrial oxaloacetate to complete this non-canonical TCA cycle. Manipulating the expression of ATP citrate lyase or the canonical TCA-cycle enzyme aconitase 2 in mouse myoblasts and embryonic stem cells revealed that changes in the configuration of the TCA cycle accompany cell fate transitions. During exit from pluripotency, embryonic stem cells switch from canonical to non-canonical TCA-cycle metabolism. Accordingly, blocking the non-canonical TCA cycle prevents cells from exiting pluripotency. These results establish a context-dependent alternative to the traditional TCA cycle and reveal that appropriate TCA-cycle engagement is required for changes in cell state.

DOI: https://doi.org/10.1038/s41586-022-04475-w
Biochim Biophys Acta Rev Cancer. 2022 Mar 08. pii: S0304-419X(22)00030-0. [Epub ahead of print] 188705

Metabolic tricks of cancer cells.

Katerina Hönigova, Jiri Navratil, Barbora Peltanova, Hana Holcova Polanska, Martina Raudenska, Michal Masarik.

  One of the characteristics of cancer cells important for tumorigenesis is their metabolic plasticity. Indeed, in various stress conditions, cancer cells can reshape their metabolic pathways to support the increased energy request due to continuous growth and rapid proliferation. Moreover, selective pressures in the tumor microenvironment, such as hypoxia, acidosis, and competition for resources, force cancer cells to adapt by complete reorganization of their metabolism. In this review, we highlight the characteristics of cancer metabolism and discuss its clinical significance, since overcoming metabolic plasticity of cancer cells is a key objective of modern cancer therapeutics and a better understanding of metabolic reprogramming may lead to the identification of possible targets for cancer therapy.

Keywords:  Cancer metabolism; Cell death; Glutaminolysis; Metabolic symbiosis; Mitochondrial bioenergetics; Warburg effect

DOI:  https://doi.org/10.1016/j.bbcan.2022.188705
Mol Cancer Ther. 2022 Feb 28. pii: molcanther.0925.2021. [Epub ahead of print]

Diaminobutoxy-substituted Isoflavonoid (DBI-1) Enhances the Therapeutic Efficacy of GLUT1 inhibitor BAY-876 by Modulating Metabolic Pathways in Colon Cancer Cells.

Lichao Guo, Wen Zhang, Yanqi Xie, Xi Chen, Emma E Olmstead, Mengqiang Lian, Baochen Zhang, Yekaterina Y Zaytseva, B Mark Evers, H Peter Spielmann, Xifu Liu, David S Watt, Chunming Liu.

Cancer cells undergo significant "metabolic remodeling" to provide sufficient ATP to maintain cell survival and to promote rapid growth. In colorectal cancer (CRC) cells, ATP is produced by mitochondrial oxidative phosphorylation (OXPHOS) and by substantially elevated cytoplasmic glucose fermentation (i.e., the Warburg effect). Glucose transporter 1 (GLUT1) expression is significantly increased in CRC cells, and GLUT1 inhibitors block glucose uptake and hence glycolysis crucial for cancer cell growth. In addition to ATP, these metabolic pathways also provide macromolecule building blocks and signaling molecules required for tumor growth. In this study, we identify a diaminobutoxy-substituted isoflavonoid (DBI-1) that inhibits mitochondrial complex I and deprives rapidly growing cancer cells of energy needed for growth. DBI-1 and the GLUT1 inhibitor, BAY-876, synergistically inhibit CRC cell growth in vitro and in vivo. This study suggests that an electron transport chain (ETC) inhibitor (i.e. DBI-1) and a glucose transport inhibitor, (i.e. BAY-876) are potentially effective combination for CRC treatment.

DOI: https://doi.org/10.1158/1535-7163.MCT-21-0925
Drug Resist Updat. 2022 Mar;pii: S1368-7646(22)00021-8. [Epub ahead of print]61 100822

Targeting metabolism to overcome cancer drug resistance: A promising therapeutic strategy for diffuse large B cell lymphoma.

Manfei Pi, Huixian Kuang, Chunyan Yue, Qixuan Yang, Anqin Wu, Yuhua Li, Yehuda G Assaraf, Dong-Hua Yang, Shaojie Wu.

  Cancer cell metabolism including aerobic glycolysis, amino acid and fatty acid metabolism, has been extensively studied. Metabolic reprogramming is a major hallmark of cancer, which promotes cancer cell proliferation, progression and metastasis, as well as provokes resistance to chemotherapeutic drugs. Several signal transduction pathways, such as BCR, MEK/ERK, Notch, NF-κB and PI3K/AKT/mTOR, regulate tumor metabolism, hence promoting tumor cell growth, proliferation and progression. Therefore, targeting metabolic enzymes, metabolites or their signal transduction pathways may constitute a promising therapeutic strategy to enhance cancer treatment efficacy. Diffuse large B-cell lymphoma (DLBCL) is the most aggressive form of non-Hodgkin lymphoma (NHL), and one-third of DLBCL patients suffer from relapsed/refractory disease after chemotherapy. The mechanisms underlying drug resistance are complex, including target gene mutations, metabolic reprogramming, aberrant signal transduction pathways, enhanced drug efflux via overexpression of multidrug efflux transporters like P-glycoprotein, upregulation of anti-apoptotic proteins, drug sequestration and enhanced DND repair. This review delineates the distinct metabolic reprogramming patterns and the association between metabolism and anticancer drug resistance in DLBCL as well as the emerging strategies to surmount chemoresistance in DLBCL.

Keywords:  cancer drug resistance; diffuse large B cell lymphoma; tumor metabolism

DOI:  https://doi.org/10.1016/j.drup.2022.100822
J Exp Clin Cancer Res. 2022 Mar 10. 41(1): 90

Brucein D augments the chemosensitivity of gemcitabine in pancreatic cancer via inhibiting the Nrf2 pathway.

Juan Zhang, Hong-Xi Xu, William Chi Shing Cho, Wah Cheuk, Yang Li, Qiong-Hui Huang, Wen Yang, Yan-Fang Xian, Zhi-Xiu Lin.

   BACKGROUND: Gemcitabine (GEM) is the first-line chemotherapeutic drug used to treat pancreatic ductal adenocarcinoma carcinoma (PDAC), but chemoresistance is often encountered clinically. Nrf2, an oxidative stress responsive transcription factor, is an important contributor to chemoresistance and poor prognosis of PDAC. Brucein D (BD), a naturally occurring quassinoid, has been reported to exert anti-tumor effect in several cancers including PDAC. In this study, we aimed to investigate the efficacy of BD and the role of Nrf2 axes on the chemosensitivity of GEM and elucidate the underlying molecular mechanisms.
METHODS: Analyses of clinical samples of PDAC and GEPIA database were first conducted to identify the expression of Nrf2 in PDAC. We then established cell lines with stable deletion of Nrf2 through transfecting lentivirus into PDAC cells. Quantitative real-time PCR (qRT-PCR) and Western blotting were performed to determine the expression of Nrf2 in these cell lines. The effects of BD and Nrf2 axes on PDAC cell proliferation, colony-formation, tumor growth and chemosensitivity were determined both in vitro and in vivo. Orthotopic xenograft and genetically engineered KPC mouse models of PDAC were used to evaluate the anti-pancreatic cancer effects of BD and GEM.
RESULTS: Nrf2 was highly expressed in PDAC in the clinical samples and GEPIA analysis. Gain- and lost-function study demonstrated that Nrf2 affected the chemosensitivity of GEM on PDAC cells both in vitro and in vivo. We further found that BD effectively inhibited PDAC cell proliferation and enhanced the chemosensitivity of GEM. Mechanistic studies revealed that BD sensitized GEM in PDAC cells through the ubiquitin-proteasome-dependent degradation of Nrf2, and downregulating the Nrf2 pathway. Silencing of Nrf2 plus BD treatment resulted in more potent inhibitory effects of GEM. In contrast, Nrf2 activation attenuated the chemosensitivity of GEM, indicating that the action of BD was Nrf2 dependent. Finally, the efficacy of BD alone and in combination with GEM on PDAC was validated on both orthotopic xenograft and genetically engineered KPC mouse models.
CONCLUSIONS: BD was able to enhance the chemosensitivity of GEM in PDAC through inhibition of the Nrf2 pathway. Our experimental findings indicate that BD, a potent Nrf2 inhibitor, holds promise for further development into a novel adjuvant therapy for PDAC.

Keywords:  Brucein D; Chemosensitivity; Gemcitabine; Nrf2; Pancreatic cancer

DOI:  https://doi.org/10.1186/s13046-022-02270-z
Cancer Res. 2022 Feb 28. pii: canres.CAN-21-3983-E.2021. [Epub ahead of print]

Comprehensive analysis of metabolic isozyme targets in cancer.

Michal Marczyk, Vignesh Gunasekharan, David Casadevall, Tao Qing, Julia Foldi, Raghav Sehgal, Naing Lin Shan, Kim R M Blenman, Tess A O'Meara, Sheila Umlauf, Yulia V Surovtseva, Viswanathan Muthusamy, Jesse Rinehart, Rachel J Perry, Richard Kibbey, Christos Hatzis, Lajos Pusztai.

Metabolic reprogramming is a hallmark of malignant transformation, and loss of isozyme diversity (LID) contributes to this process. Isozymes are distinct proteins that catalyze the same enzymatic reaction but can have different kinetic characteristics, subcellular localization, and tissue specificity. Cancer-dominant isozymes that catalyze rate-limiting reactions in critical metabolic processes represent potential therapeutic targets. Here we examined the isozyme expression patterns of 1,319 enzymatic reactions in 14 cancer types and their matching normal tissues using TCGA mRNA expression data to identify isozymes that become cancer dominant. Of the reactions analyzed, 357 demonstrated LID in at least one cancer type. Assessment of the expression patterns in over 600 cell lines in the cancer cell line encyclopedia showed that these reactions reflect cellular changes instead of differences in tissue composition; 50% of the LID-affected isozymes showed cancer-dominant expression in the corresponding cell lines. The functional importance of the cancer-dominant isozymes was assessed in genome-wide CRISPR and RNAi loss-of-function screens: 17% were critical for cell proliferation, indicating their potential as therapeutic targets. Lists of prioritized novel metabolic targets were developed for 14 cancer types; the most broadly shared and functionally validated target was acetyl-CoA carboxylase-1 (ACC1). Small molecule inhibition of ACC reduced breast cancer viability in vitro and suppressed tumor growth in cell line- and patient-derived xenografts in vivo. Evaluation of the effects of drug treatment revealed significant metabolic and transcriptional perturbations. Overall, this systematic analysis of isozyme expression patterns elucidates an important aspect of cancer metabolic plasticity and reveals putative metabolic vulnerabilities.

DOI: https://doi.org/10.1158/0008-5472.CAN-21-3983
Nutrients. 2022 Feb 26. pii: 997. [Epub ahead of print]14(5):

Impact of Parenteral Glutamine Supplement on Oncologic Outcomes in Patients with Nasopharyngeal Cancer Treated with Concurrent Chemoradiotherapy.

Chih-Chun Wang, Tzer-Zen Hwang, Chuan-Chien Yang, Ching-Feng Lien, Chien-Chung Wang, Yu-Chen Shih, Shyh-An Yeh, Meng-Che Hsieh.

   BACKGROUND: Oral mucositis (OM) is a common toxic side effect in nasopharyngeal carcinoma (NPC) patients receiving concurrent chemoradiotherapy (CCRT) that has a negative impact on treatment outcomes and patients' survival. Our study aimed to evaluate the impact of parenteral glutamine supplement (dipeptiven) on oncologic outcomes in patients with NPC treated with CCRT.
METHODS: Patients who were diagnosed with pathologically proved NPC and treated with CCRT were enrolled into our study. Patients were classified as dipeptiven (+) and dipeptiven (-). Oncologic outcomes were measured, and multivariate regression analysis was performed. Grade 3-4 treatment related toxicities were also documented.
RESULTS: A total of 144 patients with NPC were recruited in this study to evaluate oncologic outcomes, with 41 dipeptiven (+) and 103 dipeptiven (-). CCRT interruption rate and severe adverse effect (SAE) rate were significant lower in the dipeptiven (+) group than in the dipeptiven (-) group. The median overall survival (OS) was not mature yet in the dipeptiven (+) group and 30 months in the dipeptiven (-) group (p < 0.01). Multivariate analysis demonstrated that dipeptiven supplementation and CCRT interruption were independent predictors associated with better survival. The OS was longest in patients with a dipeptiven supplement and patients who had CCRT interruption had significantly worst OS. As for safety profiles, grade 3 to 4 adverse effects were fewer in dipeptiven (+) than in dipeptiven (-).
CONCLUSION: Dipeptiven supplementation is crucial in NPC patients treated with CCRT, which can ameliorate treatment-related toxicity and augment treatment efficacy. Further prospective clinical trials are warranted to validate our results.

Keywords:  chemoradiotherapy; dipeptiven; glutamine; nasopharyngeal carcinoma; oncologic outcomes; oral mucositis

DOI:  https://doi.org/10.3390/nu14050997
iScience. 2022 Mar 18. 25(3): 103924

Cancer progression as a learning process.

Aseel Shomar, Omri Barak, Naama Brenner.

  Drug resistance and metastasis-the major complications in cancer-both entail adaptation of cancer cells to stress, whether a drug or a lethal new environment. Intriguingly, these adaptive processes share similar features that cannot be explained by a pure Darwinian scheme, including dormancy, increased heterogeneity, and stress-induced plasticity. Here, we propose that learning theory offers a framework to explain these features and may shed light on these two intricate processes. In this framework, learning is performed at the single-cell level, by stress-driven exploratory trial-and-error. Such a process is not contingent on pre-existing pathways but on a random search for a state that diminishes the stress. We review underlying mechanisms that may support this search, and show by using a learning model that such exploratory learning is feasible in a high-dimensional system as the cell. At the population level, we view the tissue as a network of exploring agents that communicate, restraining cancer formation in health. In this view, disease results from the breakdown of homeostasis between cellular exploratory drive and tissue homeostasis.

Keywords:  Cancer systems biology; Evolutionary theories

DOI:  https://doi.org/10.1016/j.isci.2022.103924
Oxid Med Cell Longev. 2022 ;2022 9039732

Comprehensive Characterization of Metabolism-Associated Subtypes of Renal Cell Carcinoma to Aid Clinical Therapy.

Zhixian Yao, Zhong Zheng, Xinyi Zheng, Hantao Wu, Weiguang Zhao, Xingyu Mu, Feng Sun, Ke Wu, Junhua Zheng.

Renal cell carcinoma (RCC) is a disease characterized by excessive administration complexity because it exhibits extraordinary nonuniformity among distinct molecular subtypes. We herein intended to delineate the metabolic aspects of clear cell RCC (ccRCC) in terms of the gene expression profile. Recent studies have revealed that metabolic variations within tumors are related to the responsiveness to immune checkpoint inhibitor (ICI) therapy and patient prognosis. We used 100 previously reported metabolic (MTB) pathways to quantify the metabolic landscape of the 729 ccRCC patients. Three MTB subtypes were established, and the MTB scores were calculated using principal component analysis (PCA). The high MTB score group had better overall survival (OS) and was associated with higher expression of immune-checkpoint and immune-activity signatures. The opposite was true of the low MTB score group, which may explain the poor prognosis of these patients. Three ICI-treated cohorts or tyrosine kinase inhibitor (TKI) treated cohort proved that patients with higher MTB scores exhibited notable therapeutic benefits and clinical gains. This research explained that the MTB score could be applied as a powerful prognostic indicator and predictive of ICI or TKI therapy. Assessing the MTB scores in a more extended group will facilitate our perception of tumor metabolism and provide guidance for studies on targeted approaches for ccRCC patients.

DOI: https://doi.org/10.1155/2022/9039732