bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2022–04–10
eight papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul
  1. NADPH metabolism determines the leukemogenic capacity and drug resistance of AML cells.
  2. The Influence of Mitochondrial Energy and 1C Metabolism on the Efficacy of Anticancer Drugs - Exploring Potential Mechanisms of Resistance.
  3. Cancer stem cells: The adventurous journey from hematopoietic to leukemic stem cells.
  4. Vitamin D activates FBP1 to block the Warburg effect and modulate blast metabolism in acute myeloid leukemia.
  5. Metabolic profile of the Warburg effect as a tool for molecular prognosis and diagnosis of cancer.
  6. Bioenergetic and Metabolic Adaptation in Tumor Progression and Metastasis.
  7. A novel anticancer pharmacological agent targeting mitochondrial complex I.
  8. Immune evader cancer stem cells direct the perspective approaches to cancer immunotherapy.
  1. Cell Rep. 2022 Apr 05. pii: S2211-1247(22)00355-2. [Epub ahead of print]39(1): 110607
    NADPH metabolism determines the leukemogenic capacity and drug resistance of AML cells.
    Chiqi Chen, Xiaoyun Lai, Yaping Zhang, Li Xie, Zhuo Yu, Sijia Dan, Yu Jiang, Weicai Chen, Ligen Liu, Yi Yang, Dan Huang, Yuzheng Zhao, Junke Zheng.
      The mechanism by which redox metabolism regulates the fates of acute myeloid leukemia (AML) cells remains largely unknown. Using a highly sensitive, genetically encoded fluorescent sensor of nicotinamide adenine dinucleotide phosphate (NADPH), iNap1, we find three heterogeneous subpopulations of AML cells with different cytosolic NADPH levels in an MLL-AF9-induced murine AML model. The iNap1-high AML cells have enhanced proliferation capacities both in vitro and in vivo and are enriched for more functional leukemia-initiating cells than iNap1-low counterparts. The iNap1-high AML cells prefer localizing in the bone marrow endosteal niche and are resistant to methotrexate treatment. Furthermore, iNap1-high human primary AML cells have enhanced proliferation abilities both in vitro and in vivo. Mechanistically, the MTHFD1-mediated folate cycle regulates NADPH homeostasis to promote leukemogenesis and methotrexate resistance. These results provide important clues for understanding mechanisms by which redox metabolism regulates cancer cell fates and a potential metabolic target for AML treatments.
    Keywords:  CP: Cancer; NADPH metabolism; acute myeloid leukemia; endosteal niche; folate cycle; leukemia-initiating cells; metabolic sensor; methotrexate resistance; methylenetetrahydrofolate dehydrogenase; tetrahydrofolic acid; vascular niche
    DOI:  https://doi.org/10.1016/j.celrep.2022.110607
  2. Curr Med Chem. 2022 Apr 01.
    The Influence of Mitochondrial Energy and 1C Metabolism on the Efficacy of Anticancer Drugs - Exploring Potential Mechanisms of Resistance.
    Marika Franczak, Isabel Toenshoff, Gerrit Jansen, Ryszard T Smolenski, Elisa Giovannetti, Godefridus J Peters.
      Mitochondria are the main energy factory in living cells. To rapidly proliferate and metastasize, neoplastic cells increase their energy requirements. Thus, mitochondria become one of the most important organelles for them. Indeed, much research shows the interplay between cancer chemoresistance and altered mitochondrial function. In this review we focus on the differences in energy metabolism between cancer and normal cells, to better understand their resistance and how to develop drugs targeting energy metabolism and nucleotide synthesis. One of the differences between cancer and normal cells is the higher nicotinamide adenine dinucleotide (NAD+) level, a cofactor for the tricarboxylic acid cycle (TCA), which enhances their proliferation and helps cancer cells survive under hypoxic conditions. An important change is a metabolic switch, called the Warburg effect. This effect is based on the change of energy harvesting from oxygen-dependent transformation to oxidative phosphorylation (OXPHOS), adapt them to the tumor environment. Another mechanism is the high expression of one carbon (1C) metabolism enzymes. Again, this allows cancer cells to increase proliferation by producing precursors for the synthesis of nucleotides and amino acids. We reviewed drugs in clinical practice and in development targeting NAD+, OXPHOS, and 1C metabolism. Combinations of novel drugs with conventional antineoplastic agents may prove to be a promising new way of anticancer treatment.
    Keywords:  1C Metabolism; Cancer; Mitochondria; NAD+; Oxidative Phosphorylation (OXPHOS); Resistance
    DOI:  https://doi.org/10.2174/0929867329666220401110418
  3. Cell. 2022 Apr 03. pii: S0092-8674(22)00335-X. [Epub ahead of print]
    Cancer stem cells: The adventurous journey from hematopoietic to leukemic stem cells.
    Andreas Trumpp, Simon Haas.
      This year's Gairdner Foundation Award for Biomedical Research is awarded to John Dick for the discovery of leukemic stem cells and the hierarchical organization of acute myeloid leukemias. His work laid the foundation for the cancer stem cell model with numerous clinical implications for hematopoietic malignancies and solid tumors.
    DOI:  https://doi.org/10.1016/j.cell.2022.03.025
  4. Biomark Res. 2022 Apr 02. 10(1): 16
    Vitamin D activates FBP1 to block the Warburg effect and modulate blast metabolism in acute myeloid leukemia.
    Yi Xu, Christopher Hino, David J Baylink, Jeffrey Xiao, Mark E Reeves, Jiang F Zhong, Saied Mirshahidi, Huynh Cao.
      Acute myeloid leukemia (AML) has the lowest survival rate among the leukemias. Targeting intracellular metabolism and energy production in leukemic cells can be a promising therapeutic strategy for AML. Recently, we presented the successful use of vitamin D (1,25VD3) gene therapy to treat AML mouse models in vivo. In this study, recognizing the importance of 1,25VD3 as one of only 2 molecules (along with glucose) photosynthesized for energy during the beginning stage of life on this planet, we explored the functional role of 1,25VD3 in AML metabolism.Transcriptome database (RNA-seq) of four different AML cell lines revealed 17,757 genes responding to 1,25VD3-treatment. Moreover, we discovered that fructose-bisphosphatase 1 (FBP1) noticeably stands out as the only gene (out of 17,757 genes) with a 250-fold increase in gene expression, which is known to encode the key rate-limiting gluconeogenic enzyme fructose-1,6-bisphosphatase. The significant increased expression of FBP1 gene and proteins induced by 1,25VD3 was confirmed by qPCR, western blot, flow cytometry, immunocytochemistry and functional lactate assay. Additionally, 1,25VD3 was found to regulate different AML metabolic processes including gluconeogenesis, glycolysis, TCA, de novo nucleotide synthesis, etc. In summary, we provided the first evidence that 1,25 VD3-induced FBP1 overexpression might be a novel therapeutic target to block the "Warburg Effect" to reduce energy production in AML blasts.
    Keywords:  AML; FBP1; Glycolysis; Metabolism; Vitamin D; Warburg effect
    DOI:  https://doi.org/10.1186/s40364-022-00367-3
  5. Expert Rev Mol Diagn. 2022 Apr 08.
    Metabolic profile of the Warburg effect as a tool for molecular prognosis and diagnosis of cancer.
    Gerardo M Nava, Luis Alberto Madrigal Perez.
       INTRODUCTION: Adaptations of eukaryotic cells to environmental changes are important for their survival. However, under some circumstances, microenvironmental changes promote that eukaryotic cells utilize a metabolic signature resembling a unicellular organism named the Warburg effect. Most cancer cells share the Warburg effect displaying lactic fermentation and high glucose uptake. The Warburg effect also induces a metabolic rewiring stimulating glutamine consumption and lipid synthesis, also considered cancer hallmarks. Amino acid metabolism alteration due to the Warburg effect increases plasma levels of proline and branched-chain amino acids in several cancer types. Proline and lipids are probably used as electron transfer molecules in carcinogenic cells. In addition, branched-chain amino acids fuel the Krebs cycle, protein synthesis, and signaling in cancer cells.
    AREAS COVERED: This review covers how metabolomics studies describe changes in some metabolites and proteins associated with the Warburg effect and related metabolic pathways.
    EXPERT OPINION: In this review, we analyze the metabolic signature of the Warburg effect and related phenotypes and propose some Warburg effect-related metabolites and proteins (lactate, glucose uptake, glucose transporters, glutamine, branched-chain amino acids, proline, and some lipogenic enzymes) as promising cancer biomarkers.
    Keywords:  Biomarker; Warburg effect; cancer; diagnosis; metabolism; molecular prognosis
    DOI:  https://doi.org/10.1080/14737159.2022.2065196
  6. Front Oncol. 2022 ;12 857686
    Bioenergetic and Metabolic Adaptation in Tumor Progression and Metastasis.
    Patries M Herst, Georgia M Carson, David A Eccles, Michael V Berridge.
      The ability of cancer cells to adjust their metabolism in response to environmental changes is a well-recognized hallmark of cancer. Diverse cancer and non-cancer cells within tumors compete for metabolic resources. Metabolic demands change frequently during tumor initiation, progression and metastasis, challenging our quest to better understand tumor biology and develop novel therapeutics. Vascularization, physical constraints, immune responses and genetic instability promote tumor evolution resulting in immune evasion, opportunities to breach basement membrane barriers and spread through the circulation and lymphatics. In addition, the unfolded protein response linked to the ubiquitin proteasome system is a key player in addressing stoichiometric imbalances between nuclear and mitochondrially-encoded protein subunits of respiratory complexes, and nuclear-encoded mitochondrial ribosomal protein subunits. While progressive genetic changes, some of which affect metabolic adaptability, contribute to tumorigenesis and metastasis through clonal expansion, epigenetic changes are also important and more dynamic in nature. Understanding the role of stromal and immune cells in the tumor microenvironment in remodeling cancer cell energy metabolism has become an increasingly important area of research. In this perspective, we discuss the adaptations made by cancer cells to balance mitochondrial and glycolytic energy metabolism. We discuss how hypoxia and nutrient limitations affect reductive and oxidative stress through changes in mitochondrial electron transport activity. We propose that integrated responses to cellular stress in cancer cells are central to metabolic flexibility in general and bioenergetic adaptability in particular and are paramount in tumor progression and metastasis.
    Keywords:  bioenergetic flexibility; glycolysis-OXPHOS continuum; mito-nuclear gene expression; tumor microenvironment (TME); tumor progression and metastasis
    DOI:  https://doi.org/10.3389/fonc.2022.857686
  7. Trends Pharmacol Sci. 2022 Apr 02. pii: S0165-6147(22)00057-8. [Epub ahead of print]
    A novel anticancer pharmacological agent targeting mitochondrial complex I.
    Gabriela Reyes-Castellanos, Alice Carrier.
      Targeting metabolic reprogramming has proven successful in oncology, but this field requires better identification of drugs that inhibit mitochondrial metabolism in cancer cells. Recent work from Dr Wolf's group reveals that the primary target of the antitumor compound SMIP004-7 is mitochondrial complex I (NDUFS2 subunit), inhibition of which promotes anticancer immune surveillance.
    Keywords:  anticancer therapies; cancer metabolism; complex I; mitochondria; oxidative phosphorylation system; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.tips.2022.03.007
  8. Stem Cell Res Ther. 2022 Apr 08. 13(1): 150
    Immune evader cancer stem cells direct the perspective approaches to cancer immunotherapy.
    Hassan Dianat-Moghadam, Amir Mahari, Reza Salahlou, Mostafa Khalili, Mehdi Azizi, Hadi Sadeghzadeh.
      Exploration of tumor immunity leads to the development of immune checkpoint inhibitors and cell-based immunotherapies which improve the clinical outcomes in several tumor types. However, the poor clinical efficacy of these treatments observed for other tumors could be attributed to the inherent complex tumor microenvironment (TME), cellular heterogeneity, and stemness driven by cancer stem cells (CSCs). CSC-specific characteristics provide the bulk tumor surveillance and resistance to entire eradication upon conventional therapies. CSCs-immune cells crosstalk creates an immunosuppressive TME that reshapes the stemness in tumor cells, resulting in tumor formation and progression. Thus, identifying the immunological features of CSCs could introduce the therapeutic targets with powerful antitumor responses. In this review, we summarized the role of immune cells providing CSCs to evade tumor immunity, and then discussed the intrinsic mechanisms represented by CSCs to promote tumors' resistance to immunotherapies. Then, we outlined potent immunotherapeutic interventions followed by a perspective outlook on the use of nanomedicine-based drug delivery systems for controlled modulation of the immune system.
    Keywords:  CAR NK cells; CAR T cell; Cancer stem cells; Immune evasion; Nano-immunotherapy; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s13287-022-02829-9
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