bims-glucam Biomed News
on Glutamine cancer metabolism
Issue of 2021–05–02
twenty-six papers selected by
Sreeparna Banerjee, Middle East Technical University
  1. Glutaminolysis dynamics during astrocytoma progression correlates with tumor aggressiveness.
  2. Glutamine deficiency promotes stemness and chemoresistance in tumor cells through DRP1-induced mitochondrial fragmentation.
  3. Glutamine metabolism: From proliferating cells to cardiomyocytes.
  4. Uncovering Metabolic Reservoir Cycles in MYC-Transformed Lymphoma B cells Using Stable Isotope Resolved Metabolomics.
  5. Inhibition of eEF2K synergizes with glutaminase inhibitors or 4EBP1 depletion to suppress growth of triple-negative breast cancer cells.
  6. Pyruvate carboxylase and cancer progression.
  7. Dose-Dependent Carbon-Dot-Induced ROS Promote Uveal Melanoma Cell Tumorigenicity via Activation of mTOR Signaling and Glutamine Metabolism.
  8. Can small molecular inhibitors that stop de novo serine synthesis be used in cancer treatment?
  9. 13C Metabolic Flux Analysis Indicates Endothelial Cells Attenuate Metabolic Perturbations by Modulating TCA Activity.
  10. A GC-MS/Single-Cell Method to Evaluate Membrane Transporter Substrate Specificity and Signaling.
  11. Metabolites in the Tumor Microenvironment Reprogram Functions of Immune Effector Cells Through Epigenetic Modifications.
  12. Chemopreventive Effects of Dietary Isothiocyanates in Animal Models of Gastric Cancer and Synergistic Anticancer Effects With Cisplatin in Human Gastric Cancer Cells.
  13. The Role of NRF2/KEAP1 Signaling Pathway in Cancer Metabolism.
  14. First-in-human PET imaging and estimated radiation dosimetry of L-[5-11C]-glutamine in patients with metastatic colorectal cancer.
  15. Growing Human Hepatocellular Tumors Undergo a Global Metabolic Reprogramming.
  16. Interplay between Metabolism Reprogramming and Epithelial-to-Mesenchymal Transition in Cancer Stem Cells.
  17. Inhibition of Syk promotes chemical reprogramming of fibroblasts via metabolic rewiring and H2 S production.
  18. Targeting the Metabolic Adaptation of Metastatic Cancer.
  19. The role of redox system in metastasis formation.
  20. In cancer, all roads lead to NADPH.
  21. Endogenous glutamate determines ferroptosis sensitivity via ADCY10-dependent YAP suppression in lung adenocarcinoma.
  22. Oxidative Stress in Cancer Cell Metabolism.
  23. Emerging strategies for treating metastasis.
  24. Evolving concepts in NAD+ metabolism.
  25. Metabolic and hormonal remodeling of colorectal cancer cell signaling by diabetes.
  26. The metabolic adaptation mechanism of metastatic organotropism.
  1. Cancer Metab. 2021 Apr 28. 9(1): 18
    Glutaminolysis dynamics during astrocytoma progression correlates with tumor aggressiveness.
    Yollanda E Moreira Franco, Maria Jose Alves, Miyuki Uno, Isabele Fattori Moretti, Marina Trombetta-Lima, Suzana de Siqueira Santos, Ancely Ferreira Dos Santos, Gabriel Santos Arini, Mauricio S Baptista, Antonio Marcondes Lerario, Sueli Mieko Oba-Shinjo, Suely Kazue Nagahashi Marie.
       BACKGROUND: Glioblastoma is the most frequent and high-grade adult malignant central nervous system tumor. The prognosis is still poor despite the use of combined therapy involving maximal surgical resection, radiotherapy, and chemotherapy. Metabolic reprogramming currently is recognized as one of the hallmarks of cancer. Glutamine metabolism through glutaminolysis has been associated with tumor cell maintenance and survival, and with antioxidative stress through glutathione (GSH) synthesis.
    METHODS: In the present study, we analyzed the glutaminolysis-related gene expression levels in our cohort of 153 astrocytomas of different malignant grades and 22 non-neoplastic brain samples through qRT-PCR. Additionally, we investigated the protein expression profile of the key regulator of glutaminolysis (GLS), glutamate dehydrogenase (GLUD1), and glutamate pyruvate transaminase (GPT2) in these samples. We also investigated the glutathione synthase (GS) protein profile and the GSH levels in different grades of astrocytomas. The differential gene expressions were validated in silico on the TCGA database.
    RESULTS: We found an increase of glutaminase isoform 2 gene (GLSiso2) expression in all grades of astrocytoma compared to non-neoplastic brain tissue, with a gradual expression increment in parallel to malignancy. Genes coding for GLUD1 and GPT2 expression levels varied according to the grade of malignancy, being downregulated in glioblastoma, and upregulated in lower grades of astrocytoma (AGII-AGIII). Significant low GLUD1 and GPT2 protein levels were observed in the mesenchymal subtype of GBM.
    CONCLUSIONS: In glioblastoma, particularly in the mesenchymal subtype, the downregulation of both genes and proteins (GLUD1 and GPT2) increases the source of glutamate for GSH synthesis and enhances tumor cell fitness due to increased antioxidative capacity. In contrast, in lower-grade astrocytoma, mainly in those harboring the IDH1 mutation, the gene expression profile indicates that tumor cells might be sensitized to oxidative stress due to reduced GSH synthesis. The measurement of GLUD1 and GPT2 metabolic substrates, ammonia, and alanine, by noninvasive MR spectroscopy, may potentially allow the identification of IDH1mut AGII and AGIII progression towards secondary GBM.
    Keywords:  Astrocytoma progression; GBM; Glutaminolysis; IDH1 mutation; Low-grade astrocytoma
    DOI:  https://doi.org/10.1186/s40170-021-00255-8
  2. Cell Mol Life Sci. 2021 Apr 24.
    Glutamine deficiency promotes stemness and chemoresistance in tumor cells through DRP1-induced mitochondrial fragmentation.
    Parash Prasad, Sampurna Ghosh, Sib Sankar Roy.
      Glutamine is essential for maintaining the TCA cycle in cancer cells yet they undergo glutamine starvation in the core of tumors. Cancer stem cells (CSCs), responsible for tumor recurrence are often found in the nutrient limiting cores. Our study uncovers the molecular basis and cellular links between glutamine deprivation and stemness in the cancer cells. We showed that glutamine is dispensable for the survival of ovarian and colon cancer cells while it is required for their proliferation. Glutamine starvation leads to the metabolic reprogramming in tumor cells with enhanced glycolysis and unaltered oxidative phosphorylation. Production of reactive oxygen species (ROS) in glutamine limiting condition induces MAPK-ERK1/2 signaling pathway to phosphorylate dynamin-related protein-1(DRP1) at Ser616. Moreover, p-DRP1 promotes mitochondrial fragmentation and enhances numbers of CD44 and CD117/CD45 positive CSCs. Besides the established features of cancer stem cells, glutamine deprivation induces perinuclear localization of fragmented mitochondria and reduction in proliferation rate which are usually observed in CSCs. Treatment with glutaminase inhibitor (L-DON) mimics the effects of glutamine starvation without altering cell survival in in vitro as well as in in vivo model. Interestingly, the combinatorial treatment of L-DON with DRP1 inhibitor (MDiVi-1) reduces the stem cell population in tumor tissue in mouse model. Collectively our data suggest that glutamine deficiency in the core of tumors can increase the cancer stem cell population and the combination therapy with MDiVi-1 and L-DON is a useful approach to reduce CSCs population in tumor.
    Keywords:  Glutaminase; Glutamine metabolism; Mitochondrial fission; ROS; Tumor growth
    DOI:  https://doi.org/10.1007/s00018-021-03818-6
  3. Metabolism. 2021 Apr 23. pii: S0026-0495(21)00078-0. [Epub ahead of print] 154778
    Glutamine metabolism: From proliferating cells to cardiomyocytes.
    Yimin Shen, Yuhao Zhang, Wudi Li, Kaijie Chen, Meixiang Xiang, Hong Ma.
      Glutamine is a major energy source for rapidly dividing cells, such as hematopoietic stem cells and cancer cells. Reliance on glutamine is therefore regarded as a metabolic hallmark of proliferating cells. Moreover, reprogramming glutamine metabolism by various factors, including tissue type, microenvironment, pro-oncogenes, and tumor suppressor genes, can facilitate stem cell fate decisions, tumor recurrence, and drug resistance. However, the significance of glutamine metabolism in cardiomyocytes, an end-differentiated cell type, is not fully understood. Existing evidence suggests important roles of glutamine metabolism in the development of cardiovascular diseases. In this review, we have focused on glutaminolysis and its regulatory network in proliferating cells. We have summarized current findings about the role of glutamine utilization in cardiomyocytes and have discussed possibilities of targeting glutamine metabolism for the treatment of cardiovascular diseases.
    Keywords:  Cardiomyocytes; GGR; Glutamine; Proliferating cells
    DOI:  https://doi.org/10.1016/j.metabol.2021.154778
  4. Anal Biochem. 2021 Apr 21. pii: S0003-2697(21)00107-X. [Epub ahead of print] 114206
    Uncovering Metabolic Reservoir Cycles in MYC-Transformed Lymphoma B cells Using Stable Isotope Resolved Metabolomics.
    Giang Hoang, Cissy Zhang, Nabeel Attarwala, Jin G Jung, Arthur J L Cooper, Anne Le.
      The use of metabolomics technologies and stable isotope labeling recently enabled us to discover an unexpected role of N-acetyl-aspartyl-glutamate (NAAG): NAAG is a glutamate reservoir for cancer cells. In the current study, we first found that glucose carbon contributes to the formation of NAAG and its precursors via glycolysis, demonstrating the existence of a glucose-NAAG-glutamate cycle in cancer cells. Second, we found that glucose carbon and, unexpectedly, glutamine carbon contribute to the formation of lactate via glutaminolysis. Importantly, lactate carbon can be incorporated into glucose via gluconeogenesis, demonstrating the existence of a glutamine-lactate-glucose cycle. While a glucose-lactate-glucose cycle was expected, the finding of a glutamine-lactate-glucose cycle was unforeseen. And third, we discovered that glutamine carbon is incorporated into γ-aminobutyric acid (GABA), revealing a glutamate-GABA-succinate cycle. Thus, NAAG, lactate, and GABA can play important roles as storage molecules for glutamate, glucose, and succinate carbon in oncogenic MYC-transformed P493 lymphoma B cells (MYC-ON cells) but not in non-oncogenic MYC-OFF cells. Altogether, examining the isotopic labeling patterns of metabolites derived from labeled 13C6-glucose or 13C515N2-glutamine helped reveal the presence of what we have named "metabolic reservoir cycles" in oncogenic cells.
    Keywords:  GABA; Metabolic reservoir cycles; NAAG; lactate; oncogenic cells; storage molecules
    DOI:  https://doi.org/10.1016/j.ab.2021.114206
  5. Sci Rep. 2021 Apr 28. 11(1): 9181
    Inhibition of eEF2K synergizes with glutaminase inhibitors or 4EBP1 depletion to suppress growth of triple-negative breast cancer cells.
    YoungJun Ju, Yaacov Ben-David, Daniela Rotin, Eldad Zacksenhaus.
      The eukaryotic elongation factor-2 kinase, eEF2K, which restricts protein translation elongation, has been identified as a potential therapeutic target for diverse types of malignancies including triple negative breast cancer (TNBC). However, the contexts in which eEF2K inhibition is essential in TNBC and its consequences on the proteome are largely unknown. Here we show that genetic or pharmacological inhibition of eEF2K cooperated with glutamine (Gln) starvation, and synergized with glutaminase (GLS1) inhibitors to suppress growth of diverse TNBC cell lines. eEF2K inhibition also synergized with depletion of eukaryotic translation initiation factor 4E-binding protein 1 (eIF4EBP1; 4EBP1), a suppressor of eukaryotic protein translation initiation factor 4E (eIF4E), to induce c-MYC and Cyclin D1 expression, yet attenuate growth of TNBC cells. Proteomic analysis revealed that whereas eEF2K depletion alone uniquely induced Cyclin Dependent Kinase 1 (CDK1) and 6 (CDK6), combined depletion of eEF2K and 4EBP1 resulted in overlapping effects on the proteome, with the highest impact on the 'Collagen containing extracellular matrix' pathway (e.g. COL1A1), as well as the amino-acid transporter, SLC7A5/LAT1, suggesting a regulatory loop via mTORC1. In addition, combined depletion of eEF2K and 4EBP1 indirectly reduced the levels of IFN-dependent innate immune response-related factors. Thus, eEF2K inhibition triggers cell cycle arrest/death under unfavourable metabolic conditions such as Gln-starvation/GLS1 inhibition or 4EBP1 depletion, uncovering new therapeutic avenues for TNBC and underscoring a pressing need for clinically relevant eEF2K inhibitors.
    DOI:  https://doi.org/10.1038/s41598-021-88816-1
  6. Cancer Metab. 2021 Apr 30. 9(1): 20
    Pyruvate carboxylase and cancer progression.
    Violet A Kiesel, Madeline P Sheeley, Michael F Coleman, Eylem Kulkoyluoglu Cotul, Shawn S Donkin, Stephen D Hursting, Michael K Wendt, Dorothy Teegarden.
      Pyruvate carboxylase (PC) is a mitochondrial enzyme that catalyzes the ATP-dependent carboxylation of pyruvate to oxaloacetate (OAA), serving to replenish the tricarboxylic acid (TCA) cycle. In nonmalignant tissue, PC plays an essential role in controlling whole-body energetics through regulation of gluconeogenesis in the liver, synthesis of fatty acids in adipocytes, and insulin secretion in pancreatic β cells. In breast cancer, PC activity is linked to pulmonary metastasis, potentially by providing the ability to utilize glucose, fatty acids, and glutamine metabolism as needed under varying conditions as cells metastasize. PC enzymatic activity appears to be of particular importance in cancer cells that are unable to utilize glutamine for anaplerosis. Moreover, PC activity also plays a role in lipid metabolism and protection from oxidative stress in cancer cells. Thus, PC activity may be essential to link energy substrate utilization with cancer progression and to enable the metabolic flexibility necessary for cell resilience to changing and adverse conditions during the metastatic process.
    Keywords:  Energy metabolism; Metastasis; Pyruvate carboxylase
    DOI:  https://doi.org/10.1186/s40170-021-00256-7
  7. Adv Sci (Weinh). 2021 Apr;8(8): 2002404
    Dose-Dependent Carbon-Dot-Induced ROS Promote Uveal Melanoma Cell Tumorigenicity via Activation of mTOR Signaling and Glutamine Metabolism.
    Yi Ding, Jie Yu, Xingyu Chen, Shaoyun Wang, Zhaoxu Tu, Guangxia Shen, Huixue Wang, Renbing Jia, Shengfang Ge, Jing Ruan, Kam W Leong, Xianqun Fan.
      Uveal melanoma (UM) is the most common intraocular malignant tumor in adults and has a low survival rate following metastasis; it is derived from melanocytes susceptible to reactive oxygen species (ROS). Carbon dot (Cdot) nanoparticles are a promising tool in cancer detection and therapy due to their unique photophysical properties, low cytotoxicity, and efficient ROS productivity. However, the effects of Cdots on tumor metabolism and growth are not well characterized. Here, the effects of Cdots on UM cell metabolomics, growth, invasiveness, and tumorigenicity are investigated in vitro and in vivo zebrafish and nude mouse xenograft model. Cdots dose-dependently increase ROS levels in UM cells. At Cdots concentrations below 100 µg mL-1, Cdot-induced ROS promote UM cell growth, invasiveness, and tumorigenicity; at 200 µg mL-1, UM cells undergo apoptosis. The addition of antioxidants reverses the protumorigenic effects of Cdots. Cdots at 25-100 µg mL-1 activate Akt/mammalian target of rapamycin (mTOR) signaling and enhance glutamine metabolism, generating a cascade that promotes UM cell growth. These results demonstrate that moderate, subapoptotic doses of Cdots can promote UM cell tumorigenicity. This study lays the foundation for the rational application of ROS-producing nanoparticles in tumor imaging and therapy.
    Keywords:  ROS; glutamine; mTOR; metabolomics; uveal melanoma
    DOI:  https://doi.org/10.1002/advs.202002404
  8. Cell Death Discov. 2021 Apr 30. 7(1): 87
    Can small molecular inhibitors that stop de novo serine synthesis be used in cancer treatment?
    Megan Jessica McNamee, David Michod, Maria Victoria Niklison-Chirou.
      To sustain their malignancy, tumour cells acquire several metabolic adaptations such as increased oxygen, glucose, glutamine, and lipids uptake. Other metabolic processes are also enhanced as part of tumour metabolic reprogramming, for example, increased serine metabolism. Serine is a non-essential amino acid that supports several metabolic processes that are crucial for the growth and survival of proliferating cells, including protein, DNA, and glutathione synthesis. Indeed, increased activity of D-3-phosphoglycerate dehydrogenase (PHGDH), the enzyme rate-limiting de novo serine synthesis, has been extensively reported in several tumours. Therefore, selective inhibition of PHGDH may represent a new therapeutic strategy for over-expressing PHGDH tumours, owing to its downstream inhibition of essential biomass production such as one-carbon units and nucleotides. This perspective article will discuss the current status of research into small molecular inhibitors against PHGDH in colorectal cancer, breast cancer, and Ewing's sarcoma. We will summarise recent studies on the development of PHGDH-inhibitors, highlighting their clinical potential as new therapeutics. It also wants to shed a light on some of the key limitations of the use of PHGDH-inhibitors in cancer treatment which are worth taking into account.
    DOI:  https://doi.org/10.1038/s41420-021-00474-4
  9. Metabolites. 2021 Apr 07. pii: 226. [Epub ahead of print]11(4):
    13C Metabolic Flux Analysis Indicates Endothelial Cells Attenuate Metabolic Perturbations by Modulating TCA Activity.
    Bilal Moiz, Jonathan Garcia, Sarah Basehore, Angela Sun, Andrew Li, Surya Padmanabhan, Kaitlyn Albus, Cholsoon Jang, Ganesh Sriram, Alisa Morss Clyne.
      Disrupted endothelial metabolism is linked to endothelial dysfunction and cardiovascular disease. Targeted metabolic inhibitors are potential therapeutics; however, their systemic impact on endothelial metabolism remains unknown. In this study, we combined stable isotope labeling with 13C metabolic flux analysis (13C MFA) to determine how targeted inhibition of the polyol (fidarestat), pentose phosphate (DHEA), and hexosamine biosynthetic (azaserine) pathways alters endothelial metabolism. Glucose, glutamine, and a four-carbon input to the malate shuttle were important carbon sources in the baseline human umbilical vein endothelial cell (HUVEC) 13C MFA model. We observed two to three times higher glutamine uptake in fidarestat and azaserine-treated cells. Fidarestat and DHEA-treated HUVEC showed decreased 13C enrichment of glycolytic and TCA metabolites and amino acids. Azaserine-treated HUVEC primarily showed 13C enrichment differences in UDP-GlcNAc. 13C MFA estimated decreased pentose phosphate pathway flux and increased TCA activity with reversed malate shuttle direction in fidarestat and DHEA-treated HUVEC. In contrast, 13C MFA estimated increases in both pentose phosphate pathway and TCA activity in azaserine-treated cells. These data show the potential importance of endothelial malate shuttle activity and suggest that inhibiting glycolytic side branch pathways can change the metabolic network, highlighting the need to study systemic metabolic therapeutic effects.
    Keywords:  aldose reductase inhibitors; cardiovascular disease; endothelial metabolism; fluxomics; hexosamine biosynthetic pathway; metabolic flux analysis; pentose phosphate pathway; polyol pathway
    DOI:  https://doi.org/10.3390/metabo11040226
  10. Front Mol Biosci. 2021 ;8 646574
    A GC-MS/Single-Cell Method to Evaluate Membrane Transporter Substrate Specificity and Signaling.
    Stephen J Fairweather, Shoko Okada, Gregory Gauthier-Coles, Kiran Javed, Angelika Bröer, Stefan Bröer.
      Amino acid transporters play a vital role in metabolism and nutrient signaling pathways. Typically, transport activity is investigated using single substrates and competing amounts of other amino acids. We used GC-MS and LC-MS for metabolic screening of Xenopus laevis oocytes expressing various human amino acid transporters incubated in complex media to establish their comprehensive substrate profiles. For most transporters, amino acid selectivity matched reported substrate profiles. However, we could not detect substantial accumulation of cationic amino acids by SNAT4 and ATB0,+ in contrast to previous reports. In addition, comparative substrate profiles of two related sodium neutral amino acid transporters known as SNAT1 and SNAT2, revealed the latter as a significant leucine accumulator. As a consequence, SNAT2, but not SNAT1, was shown to be an effective activator of the eukaryotic cellular growth regulator mTORC1. We propose, that metabolomic profiling of membrane transporters in Xe nopus laevis oocytes can be used to test their substrate specificity and role in intracellular signaling pathways.
    Keywords:  GC-MS; SNAT2; Xenopus laevis oocytes; amino acid signaling; amino acid transporters; mTORC1 signaling; metabolomics; slc38a2
    DOI:  https://doi.org/10.3389/fmolb.2021.646574
  11. Front Immunol. 2021 ;12 641883
    Metabolites in the Tumor Microenvironment Reprogram Functions of Immune Effector Cells Through Epigenetic Modifications.
    Yijia Li, Yangzhe Wu, Yi Hu.
      Cellular metabolism of both cancer and immune cells in the acidic, hypoxic, and nutrient-depleted tumor microenvironment (TME) has attracted increasing attention in recent years. Accumulating evidence has shown that cancer cells in TME could outcompete immune cells for nutrients and at the same time, producing inhibitory products that suppress immune effector cell functions. Recent progress revealed that metabolites in the TME could dysregulate gene expression patterns in the differentiation, proliferation, and activation of immune effector cells by interfering with the epigenetic programs and signal transduction networks. Nevertheless, encouraging studies indicated that metabolic plasticity and heterogeneity between cancer and immune effector cells could provide us the opportunity to discover and target the metabolic vulnerabilities of cancer cells while potentiating the anti-tumor functions of immune effector cells. In this review, we will discuss the metabolic impacts on the immune effector cells in TME and explore the therapeutic opportunities for metabolically enhanced immunotherapy.
    Keywords:  anti-tumor immunity; epigenetic modifications; immune cell reprogramming; metabolites; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2021.641883
  12. Front Pharmacol. 2021 ;12 613458
    Chemopreventive Effects of Dietary Isothiocyanates in Animal Models of Gastric Cancer and Synergistic Anticancer Effects With Cisplatin in Human Gastric Cancer Cells.
    Hanne-Line Rabben, Yosuke Kodama, Masahiko Nakamura, Atle Magnar Bones, Timothy Cragin Wang, Duan Chen, Chun-Mei Zhao, Anders Øverby.
      Naturally occurring isothiocyanates (ITCs) from edible vegetables have shown potential as chemopreventive agents against several types of cancer. The aims of the present study were to study the potential of ITCs in chemoprevention and in potentiating the efficacy of cytotoxic drugs in gastric cancer treatment. The chemoprevention was studied in chemically induced mouse model of gastric cancer, namely N-methyl-N-nitrosourea (MNU) in drinking water, and in a genetically engineered mouse model of gastric cancer (the so-called INS-GAS mice). The pharmacological effects of ITCs with or without cisplatin were studied in human gastric cell lines MKN45, AGS, MKN74 and KATO-III, which were derived from either intestinal or diffused types of gastric carcinoma. The results showed that dietary phenethyl isothiocyanate (PEITC) reduced the tumor size when PEITC was given simultaneously with MNU, but neither when administrated after MNU nor in INS-GAS mice. Treatments of gastric cancer cells with ITCs resulted in a time- and concentration-dependent inhibition on cell proliferation. Pretreatment of gastric cancer cells with ITCs enhanced the inhibitory effects of cisplatin (but not 5-fluorouracil) in time- and concentration-dependent manners. Treatments of gastric cancer cells with PEITC plus cisplatin simultaneously at different concentrations of either PEITC or cisplatin exhibited neither additive nor synergetic inhibitory effect. Furthermore, PEITC depleted glutathione and induced G2/M cell cycle arrest in gastric cancer cells. In conclusion, the results of the present study showed that PEITC displayed anti-cancer effects, particularly when given before the tumor initiation, suggesting a chemopreventive effect in gastric cancer, and that pretreatment of PEITC potentiated the anti-cancer effects of cisplatin, possibly by reducing the intracellular pool of glutathione, suggesting a possible combination strategy of chemotherapy with pretreatment with PEITC.
    Keywords:  cisplatin; dietary (or plant) isothiocyanates; gastric cancer; glutamine; glutathione; mice
    DOI:  https://doi.org/10.3389/fphar.2021.613458
  13. Int J Mol Sci. 2021 Apr 22. pii: 4376. [Epub ahead of print]22(9):
    The Role of NRF2/KEAP1 Signaling Pathway in Cancer Metabolism.
    Moon-Young Song, Da-Young Lee, Kyung-Soo Chun, Eun-Hee Kim.
      The nuclear factor-erythroid 2 p45-related factor 2 (NRF2, also called Nfe2l2) and its cytoplasmic repressor, Kelch-like ECH-associated protein 1 (KEAP1), are major regulators of redox homeostasis controlling a multiple of genes for detoxification and cytoprotective enzymes. The NRF2/KEAP1 pathway is a fundamental signaling cascade responsible for the resistance of metabolic, oxidative stress, inflammation, and anticancer effects. Interestingly, a recent accumulation of evidence has indicated that NRF2 exhibits an aberrant activation in cancer. Evidence has shown that the NRF2/KEAP1 signaling pathway is associated with the proliferation of cancer cells and tumerigenesis through metabolic reprogramming. In this review, we provide an overview of the regulatory molecular mechanism of the NRF2/KEAP1 pathway against metabolic reprogramming in cancer, suggesting that the regulation of NRF2/KEAP1 axis might approach as a novel therapeutic strategy for cancers.
    Keywords:  KEAP1; NRF2; cancer metabolism; metabolic reprogramming
    DOI:  https://doi.org/10.3390/ijms22094376
  14. J Nucl Med. 2021 Apr 30. pii: jnumed.120.261594. [Epub ahead of print]
    First-in-human PET imaging and estimated radiation dosimetry of L-[5-11C]-glutamine in patients with metastatic colorectal cancer.
    Allison S Cohen, Joe Grudzinski, Gary T Smith, Todd E Peterson, Jennifer G Whisenant, Tiffany L Hickman, Kristen K Ciombor, Dana Cardin, Cathy Eng, Laura W Goff, Satya Das, Robert J Coffey, Jordan D Berlin, Henry Charles Manning.
      Altered metabolism is a hallmark of cancer. In addition to glucose, glutamine is an important nutrient for cellular growth and proliferation. Non-invasive imaging via positron emission tomography (PET) may help facilitate precision treatment of cancer through patient selection and monitoring of treatment response. L-[5-11C]-glutamine (11C-glutamine) is a PET tracer designed to study glutamine uptake and metabolism. The aim of this first-in-human study was to evaluate the radiologic safety and biodistribution of 11C-glutamine for oncologic PET imaging. Methods: Nine patients with confirmed metastatic colorectal cancer underwent PET/computed tomography (CT) imaging. Patients received 337.97 ± 44.08 MBq of 11C-glutamine. Dynamic PET acquisitions centered over the abdomen or thorax were initiated simultaneously with intravenous tracer administration. Following the dynamic acquisition, a whole-body PET/CT was acquired. Volume-of-interest analyses were carried out to obtain estimates of organ-based absorbed doses of radiation. Results: 11C-glutamine was well-tolerated in all patients with no observed safety concerns. Organs with the highest radiation exposure included the bladder, pancreas, and liver. The estimated effective dose was 4.46E-03 ± 7.67E-04 mSv/MBq. Accumulation of 11C-glutamine was elevated and visualized in lung, brain, bone, and liver metastases, suggesting utility for cancer imaging. Conclusion: PET using 11C-glutamine appears safe for human use and allows non-invasive visualization of metastatic colon cancer lesions in multiple organs. Further studies are needed to elucidate its potential for other cancers and for monitoring response to treatment.
    Keywords:  11C-glutamine; Colorectal cancer; Metabolism; Oncology: General; PET; PET/CT; Radiopharmaceuticals
    DOI:  https://doi.org/10.2967/jnumed.120.261594
  15. Cancers (Basel). 2021 Apr 20. pii: 1980. [Epub ahead of print]13(8):
    Growing Human Hepatocellular Tumors Undergo a Global Metabolic Reprogramming.
    Fangrong Zhang, Yingchao Wang, Geng Chen, Zhenli Li, Xiaohua Xing, Csilla Putz-Bankuti, Rudolf E Stauber, Xiaolong Liu, Tobias Madl.
      Hepatocellular carcinoma (HCC) is a common malignancy with poor prognosis, high morbidity and mortality concerning with lack of effective diagnosis and high postoperative recurrence. Similar with other cancers, HCC cancer cells have to alter their metabolism to adapt to the changing requirements imposed by the environment of the growing tumor. In less vascularized regions of tumor, cancer cells experience hypoxia and nutrient starvation. Here, we show that HCC undergoes a global metabolic reprogramming during tumor growth. A combined proteomics and metabolomics analysis of paired peritumoral and tumor tissues from 200 HCC patients revealed liver-specific metabolic reprogramming and metabolic alterations with increasing tumor sizes. Several proteins and metabolites associated with glycolysis, the tricarboxylic acid cycle and pyrimidine synthesis were found to be differentially regulated in serum, tumor and peritumoral tissue with increased tumor sizes. Several prognostic metabolite biomarkers involved in HCC metabolic reprogramming were identified and integrated with clinical and pathological data. We built and validated this combined model to discriminate against patients with different recurrence risks. An integrated and comprehensive metabolomic analysis of HCC is provided by our present work. Metabolomic alterations associated with the advanced stage of the disease and poor clinical outcomes, were revealed. Targeting cancer metabolism may deliver effective therapies for HCC.
    Keywords:  NMR spectroscopy; hepatocellular carcinoma; metabolomics; predictive model; proteomics
    DOI:  https://doi.org/10.3390/cancers13081980
  16. Cancers (Basel). 2021 Apr 20. pii: 1973. [Epub ahead of print]13(8):
    Interplay between Metabolism Reprogramming and Epithelial-to-Mesenchymal Transition in Cancer Stem Cells.
    Yoann Daniel, Elise Lelou, Caroline Aninat, Anne Corlu, Florian Cabillic.
      Tumor cells display important plasticity potential, which contributes to intratumoral heterogeneity. Notably, tumor cells have the ability to retrodifferentiate toward immature states under the influence of their microenvironment. Importantly, this phenotypical conversion is paralleled by a metabolic rewiring, and according to the metabostemness theory, metabolic reprogramming represents the first step of epithelial-to-mesenchymal transition (EMT) and acquisition of stemness features. Most cancer stem cells (CSC) adopt a glycolytic phenotype even though cells retain functional mitochondria. Such adaptation is suggested to reduce the production of reactive oxygen species (ROS), protecting CSC from detrimental effects of ROS. CSC may also rely on glutaminolysis or fatty acid metabolism to sustain their energy needs. Besides pro-inflammatory cytokines that are well-known to initiate the retrodifferentiation process, the release of catecholamines in the microenvironment of the tumor can modulate both EMT and metabolic changes in cancer cells through the activation of EMT transcription factors (ZEB1, Snail, or Slug (SNAI2)). Importantly, the acquisition of stem cell properties favors the resistance to standard care chemotherapies. Hence, a better understanding of this process could pave the way for the development of therapies targeting CSC metabolism, providing new strategies to eradicate the whole tumor mass in cancers with unmet needs.
    Keywords:  cancer stem cell; catecholamines; cell plasticity; epithelial-to-mesenchymal transition; metabolism reprogramming
    DOI:  https://doi.org/10.3390/cancers13081973
  17. EMBO J. 2021 Apr 28. e106771
    Inhibition of Syk promotes chemical reprogramming of fibroblasts via metabolic rewiring and H2 S production.
    Weiyun Wang, Shaofang Ren, Yunkun Lu, Xi Chen, Juanjuan Qu, Xiaojie Ma, Qian Deng, Zhensheng Hu, Yan Jin, Ziyu Zhou, Wenyan Ge, Yibing Zhu, Nannan Yang, Qin Li, Jiaqi Pu, Guo Chen, Cunqi Ye, Hao Wang, Xiaoyang Zhao, Zhiqiang Liu, Saiyong Zhu.
      Chemical compounds have recently been introduced as alternative and non-integrating inducers of pluripotent stem cell fate. However, chemical reprogramming is hampered by low efficiency and the molecular mechanisms remain poorly characterized. Here, we show that inhibition of spleen tyrosine kinase (Syk) by R406 significantly promotes mouse chemical reprogramming. Mechanistically, R406 alleviates Syk / calcineurin (Cn) / nuclear factor of activated T cells (NFAT) signaling-mediated suppression of glycine, serine, and threonine metabolic genes and dependent metabolites. Syk inhibition upregulates glycine level and downstream transsulfuration cysteine biosynthesis, promoting cysteine metabolism and cellular hydrogen sulfide (H2 S) production. This metabolic rewiring decreased oxidative phosphorylation and ROS levels, enhancing chemical reprogramming. In sum, our study identifies Syk-Cn-NFAT signaling axis as a new barrier of chemical reprogramming and suggests metabolic rewiring and redox homeostasis as important opportunities for controlling cell fates.
    Keywords:  R406; Syk; chemical reprogramming; hydrogen sulfide; metabolism
    DOI:  https://doi.org/10.15252/embj.2020106771
  18. Cancers (Basel). 2021 Apr 01. pii: 1641. [Epub ahead of print]13(7):
    Targeting the Metabolic Adaptation of Metastatic Cancer.
    Josep Tarragó-Celada, Marta Cascante.
      Metabolic adaptation is emerging as an important hallmark of cancer and metastasis. In the last decade, increasing evidence has shown the importance of metabolic alterations underlying the metastatic process, especially in breast cancer metastasis but also in colorectal cancer metastasis. Being the main cause of cancer-related deaths, it is of great importance to developing new therapeutic strategies that specifically target metastatic cells. In this regard, targeting metabolic pathways of metastatic cells is one of the more promising windows for new therapies of metastatic colorectal cancer, where still there are no approved inhibitors against metabolic targets. In this study, we review the recent advances in the field of metabolic adaptation of cancer metastasis, focusing our attention on colorectal cancer. In addition, we also review the current status of metabolic inhibitors for cancer treatment.
    Keywords:  colon cancer; metabolism; metastasis
    DOI:  https://doi.org/10.3390/cancers13071641
  19. Angiogenesis. 2021 Apr 28.
    The role of redox system in metastasis formation.
    Chiara Cencioni, Valentina Comunanza, Emanuele Middonti, Edoardo Vallariello, Federico Bussolino.
      The metastatic cancer disease represents the real and urgent clinical need in oncology. Therefore, an understanding of the complex molecular mechanisms sustaining the metastatic cascade is critical to advance cancer therapies. Recent studies highlight how redox signaling influences the behavior of metastatic cancer cells, contributes to their travel in bloodstream from the primary tumor to the distant organs and conditions the progression of the micrometastases or their dormant state. Radical oxygen species not only regulate intracellular processes but participate to paracrine circuits by diffusion to nearby cells, thus assuming unpredicted roles in the communication between metastatic cancer cells, blood circulating cells, and stroma cells at site of colonization. Here, we review recent insights in the role of radical oxygen species in the metastasis formation with a special focus on extravasation at metastatic sites.
    Keywords:  Endothelial cells; Metastatic cancer cells; Neutrophils; Platelets
    DOI:  https://doi.org/10.1007/s10456-021-09779-5
  20. Pharmacol Ther. 2021 Apr 21. pii: S0163-7258(21)00066-8. [Epub ahead of print] 107864
    In cancer, all roads lead to NADPH.
    Gulam M Rather, Alvinsyah Adhityo Pramono, Zoltan Szekely, Joseph R Bertino, Philip M Tedeschi.
      Cancer cells require increased levels of NADPH for increased nucleotide synthesis and for protection from ROS. Recent studies show that increased NADPH is generated in several ways. Activated AKT phosphorylates NAD kinase (NADK), increasing its activity. NADP formed, is rapidly converted to NADPH by glucose 6-phosphate dehydrogenase and malic enzymes, overexpressed in tumor cells with mutant p53. Calmodulin, overexpressed in some cancers, also increases NADK activity. Also, in IDH1/2 mutant cancer, NADPH serves as the cofactor to generate D-2 hydroxyglutarate, an oncometabolite. The requirement of cancer cells for elevated levels of NADPH provides an opportunity to target its synthesis for cancer treatment.
    Keywords:  Calmodulin; NAD; NAD kinase; NADPH; ROS
    DOI:  https://doi.org/10.1016/j.pharmthera.2021.107864
  21. Theranostics. 2021 ;11(12): 5650-5674
    Endogenous glutamate determines ferroptosis sensitivity via ADCY10-dependent YAP suppression in lung adenocarcinoma.
    Xiao Zhang, Keke Yu, Lifang Ma, Zijun Qian, Xiaoting Tian, Yayou Miao, Yongjie Niu, Xin Xu, Susu Guo, Yueyue Yang, Zhixian Wang, Xiangfei Xue, Chuanjia Gu, Wentao Fang, Jiayuan Sun, Yongchun Yu, Jiayi Wang.
      Rationale: Ferroptosis, a newly identified form of regulated cell death, can be induced following the inhibition of cystine-glutamate antiporter system XC - because of the impaired uptake of cystine. However, the outcome following the accumulation of endogenous glutamate in lung adenocarcinoma (LUAD) has not yet been determined. Yes-associated protein (YAP) is sustained by the hexosamine biosynthesis pathway (HBP)-dependent O-linked beta-N-acetylglucosaminylation (O-GlcNAcylation), and glutamine-fructose-6-phosphate transaminase (GFPT1), the rate-limiting enzyme of the HBP, can be phosphorylated and inhibited by adenylyl cyclase (ADCY)-mediated activation of protein kinase A (PKA). However, whether accumulated endogenous glutamate determines ferroptosis sensitivity by influencing the ADCY/PKA/HBP/YAP axis in LUAD cells is not understood. Methods: Cell viability, cell death and the generation of lipid reactive oxygen species (ROS) and malondialdehyde (MDA) were measured to evaluate the responses to the induction of ferroptosis following the inhibition of system XC -. Tandem mass tags (TMTs) were employed to explore potential factors critical for the ferroptosis sensitivity of LUAD cells. Immunoblotting (IB) and quantitative RT-PCR (qPCR) were used to analyze protein and mRNA expression. Co-immunoprecipitation (co-IP) assays were performed to identify protein-protein interactions and posttranslational modifications. Metabolite levels were measured using the appropriate kits. Transcriptional regulation was evaluated using a luciferase reporter assay, chromatin immunoprecipitation (ChIP), and electrophoretic mobility shift assay (EMSA). Drug administration and limiting dilution cell transplantation were performed with cell-derived xenograft (CDX) and patient-derived xenograft (PDX) mouse models. The associations among clinical outcome, drug efficacy and ADCY10 expression were determined based on data from patients who underwent curative surgery and evaluated with patient-derived primary LUAD cells and tissues. Results: The accumulation of endogenous glutamate following system XC - inhibition has been shown to determine ferroptosis sensitivity by suppressing YAP in LUAD cells. YAP O-GlcNAcylation and expression cannot be sustained in LUAD cells upon impairment of GFPT1. Thus, Hippo pathway-like phosphorylation and ubiquitination of YAP are enhanced. ADCY10 acts as a key downstream target and diversifies the effects of glutamate on the PKA-dependent suppression of GFPT1. We also discovered that the protumorigenic and proferroptotic effects of ADCY10 are mediated separately. Advanced-stage LUADs with high ADCY10 expression are sensitive to ferroptosis. Moreover, LUAD cells with acquired therapy resistance are also prone to higher ADCY10 expression and are more likely to respond to ferroptosis. Finally, a varying degree of secondary labile iron increase is caused by the failure to sustain YAP-stimulated transcriptional compensation for ferritin at later stages further explains why ferroptosis sensitivity varies among LUAD cells. Conclusions: Endogenous glutamate is critical for ferroptosis sensitivity following the inhibition of system XC - in LUAD cells, and ferroptosis-based treatment is a good choice for LUAD patients with later-stage and/or therapy-resistant tumors.
    Keywords:  Ferritin; GFPT1; HBP-dependent O-GlcNAcylation; Hippo pathway; NCOA4; XBP1 splicing
    DOI:  https://doi.org/10.7150/thno.55482
  22. Antioxidants (Basel). 2021 Apr 22. pii: 642. [Epub ahead of print]10(5):
    Oxidative Stress in Cancer Cell Metabolism.
    Saniya Arfin, Niraj Kumar Jha, Saurabh Kumar Jha, Kavindra Kumar Kesari, Janne Ruokolainen, Shubhadeep Roychoudhury, Brijesh Rathi, Dhruv Kumar.
      Reactive oxygen species (ROS) are important in regulating normal cellular processes whereas deregulated ROS leads to the development of a diseased state in humans including cancers. Several studies have been found to be marked with increased ROS production which activates pro-tumorigenic signaling, enhances cell survival and proliferation and drives DNA damage and genetic instability. However, higher ROS levels have been found to promote anti-tumorigenic signaling by initiating oxidative stress-induced tumor cell death. Tumor cells develop a mechanism where they adjust to the high ROS by expressing elevated levels of antioxidant proteins to detoxify them while maintaining pro-tumorigenic signaling and resistance to apoptosis. Therefore, ROS manipulation can be a potential target for cancer therapies as cancer cells present an altered redox balance in comparison to their normal counterparts. In this review, we aim to provide an overview of the generation and sources of ROS within tumor cells, ROS-associated signaling pathways, their regulation by antioxidant defense systems, as well as the effect of elevated ROS production in tumor progression. It will provide an insight into how pro- and anti-tumorigenic ROS signaling pathways could be manipulated during the treatment of cancer.
    Keywords:  NFκB pathway; angiogenesis; apoptosis; autophagy; cancer metabolism; drug resistance; metastasis; mitochondrial ROS; oxidative stress; tumor adaptation; tumor progression; tumor targeting; warburg effect
    DOI:  https://doi.org/10.3390/antiox10050642
  23. Nat Cancer. 2021 Mar;2(3): 258-270
    Emerging strategies for treating metastasis.
    Mark Esposito, Shridar Ganesan, Yibin Kang.
      The systemic spread of tumor cells is the ultimate cause of the majority of deaths from cancer, yet few successful therapeutic strategies have emerged to specifically target metastasis. Here we discuss recent advances in our understanding of tumor-intrinsic pathways driving metastatic colonization and therapeutic resistance, as well as immune activating strategies to target metastatic disease. We focus on therapeutically exploitable mechanisms, promising strategies in preclinical and clinical development, and emerging areas with potential to become innovative treatments.
    DOI:  https://doi.org/10.1038/s43018-021-00181-0
  24. Cell Metab. 2021 Apr 22. pii: S1550-4131(21)00169-8. [Epub ahead of print]
    Evolving concepts in NAD+ metabolism.
    Claudia C S Chini, Julianna D Zeidler, Sonu Kashyap, Gina Warner, Eduardo Nunes Chini.
      NAD(H) and NADP(H) have traditionally been viewed as co-factors (or co-enzymes) involved in a myriad of oxidation-reduction reactions including the electron transport in the mitochondria. However, NAD pathway metabolites have many other important functions, including roles in signaling pathways, post-translational modifications, epigenetic changes, and regulation of RNA stability and function via NAD-capping of RNA. Non-oxidative reactions ultimately lead to the net catabolism of these nucleotides, indicating that NAD metabolism is an extremely dynamic process. In fact, recent studies have clearly demonstrated that NAD has a half-life in the order of minutes in some tissues. Several evolving concepts on the metabolism, transport, and roles of these NAD pathway metabolites in disease states such as cancer, neurodegeneration, and aging have emerged in just the last few years. In this perspective, we discuss key recent discoveries and changing concepts in NAD metabolism and biology that are reshaping the field. In addition, we will pose some open questions in NAD biology, including why NAD metabolism is so fast and dynamic in some tissues, how NAD and its precursors are transported to cells and organelles, and how NAD metabolism is integrated with inflammation and senescence. Resolving these questions will lead to significant advancements in the field.
    Keywords:  NAD pathway metabolites; NAD(+); aging; disease; humans; mitochondria; transport; vitamin B3
    DOI:  https://doi.org/10.1016/j.cmet.2021.04.003
  25. Endocr Relat Cancer. 2021 Apr 01. pii: ERC-21-0092. [Epub ahead of print]
    Metabolic and hormonal remodeling of colorectal cancer cell signaling by diabetes.
    María Gutiérrez-Salmerón, Silvia Rocío Rocío Lucena, Ana Chocarro-Calvo, Jose Manuel Garcia-Martinez, Rosa M Martín Orozco, Custodia García-Jiménez.
      The existence of molecular links that facilitate colorectal cancer (CRC) development in the population with type 2 diabetes (T2D) is supported by substantial epidemiological evidence. This review summarizes how the systemic metabolic and hormonal imbalances from T2D alter CRC cell metabolism, signaling and gene expression as well as their reciprocal meshing, with an overview of CRC molecular subtypes and animal models to study the diabetes-CRC cancer links. Metabolic and growth factor checkpoints ensure a physiological cell proliferation rate compatible with limited nutrient supply. Hyperinsulinemia and hyperleptinemia in prediabetes and excess circulating glucose and lipids in T2D, overcome formidable barriers for tumor development. Increased nutrient availability favours metabolic reprogramming, alters signaling and generate mutations and epigenetic modifications, through increased reactive oxygen species and oncometabolites. The reciprocal control between metabolism and hormone signaling is lost in diabetes. Excess adipose tissue at the origin of T2D, unbalances adipokine (leptin / adiponectin) secretion ratios and function and disrupts the Insulin/IGF axes. Leptin/adiponectin imbalances in T2D are believed to promote proliferation and invasion of CRC cancer cells and contribute to inflammation, an important component of CRC tumorigenesis. Disruption of the Insulin/IGF axes in T2D targets systemic and CRC cell metabolic reprogramming, survival and proliferation. Future research to clarify the molecular diabetes-CRC links will help to prevent CRC and reduce its incidence in the diabetic population and must guide therapeutic decisions.
    DOI:  https://doi.org/10.1530/ERC-21-0092
  26. Exp Hematol Oncol. 2021 Apr 29. 10(1): 30
    The metabolic adaptation mechanism of metastatic organotropism.
    Chao Wang, Daya Luo.
      Metastasis is a complex multistep cascade of cancer cell extravasation and invasion, in which metabolism plays an important role. Recently, a metabolic adaptation mechanism of cancer metastasis has been proposed as an emerging model of the interaction between cancer cells and the host microenvironment, revealing a deep and extensive relationship between cancer metabolism and cancer metastasis. However, research on how the host microenvironment affects cancer metabolism is mostly limited to the impact of the local tumour microenvironment at the primary site. There are few studies on how differences between the primary and secondary microenvironments promote metabolic changes during cancer progression or how secondary microenvironments affect cancer cell metastasis preference. Hence, we discuss how cancer cells adapt to and colonize in the metabolic microenvironments of different metastatic sites to establish a metastatic organotropism phenotype. The mechanism is expected to accelerate the research of cancer metabolism in the secondary microenvironment, and provides theoretical support for the generation of innovative therapeutic targets for clinical metastatic diseases.
    Keywords:  Cancer metabolism; Cancer metastasis; Organotropism; “Seed and soil” hypothesis
    DOI:  https://doi.org/10.1186/s40164-021-00223-4
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