bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2022–04–24
twelve papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul
  1. Small Molecule Screening of Primary Human Acute Myeloid Leukemia Using Co-culture and Multiplexed FACS Analysis.
  2. Abnormal lipid synthesis as a therapeutic target for cancer stem cells.
  3. Energetic metabolic reprogramming in Jurkat DFF40-deficient cancer cells.
  4. [Anti-cancer properties of dichloroacetate].
  5. Mitochondrial and metabolic alterations in cancer cells.
  6. The Entanglement between Mitochondrial DNA and Tumor Metastasis.
  7. The mitochondrial pyruvate carrier regulates memory T cell differentiation and antitumor function.
  8. The paradigm of drug resistance in cancer: an epigenetic perspective.
  9. Effects of Glucose Metabolism, Lipid Metabolism, and Glutamine Metabolism on Tumor Microenvironment and Clinical Implications.
  10. Impact of Drp1-Mediated Mitochondrial Dynamics on T Cell Immune Modulation.
  11. Fifty Years of Research on Protonophores: Mitochondrial Uncoupling As a Basis for Therapeutic Action.
  12. Fight mutant cancer cells by … making more mutations?
  1. Bio Protoc. 2022 Mar 20. 12(6): e4353
    Small Molecule Screening of Primary Human Acute Myeloid Leukemia Using Co-culture and Multiplexed FACS Analysis.
    Aurélie Baudet, Simon Hultmark, Fredrik Ek, Mattias Magnusson.
      Ex vivo culture of primary acute myeloid leukemia (AML) cells is notoriously difficult due to spontaneous differentiation and cell death, which hinders mechanistic and translational studies. To overcome this bottleneck, we have implemented a co-culture system, where the OP9-M2 stromal cells support the growth, but most notably limit the differentiation of primary AML cells, thus allowing for mechanistic studies in vitro. Additionally, the co-culture on OP9-M2 stromal is superior in preserving surface marker expression of primary (adult and pediatric) AML cells in comparison to stroma-free culture. Thus, by combining the co-culture with multicolor, high-throughput FACS, we can evaluate the effect of hundreds of small molecules on multi-parametric processes including: cell survival, stemness (leukemic stem cells), and myeloid differentiation on the primary AML cells at a single-cell level. This method streamlines the identification of potential therapeutic agents, but also facilitates combinatorial screening aiming, for instance, at dissecting the regulatory pathways in a patient-specific manner. Graphic abstract: Schematic representation of the ex vivo small molecule screening of primary human acute myeloid leukemia. Irradiated, sub-confluent OP9-M2 stromal cells are plated in half-area 96 wells plates 4-16 h prior to adding primary AML cells. Compounds are added 36-48 h later and effects on cell number, leukemic stem cell population, and myeloid differentiation are quantifed by FACS after 4 days of treatment.
    Keywords:  Drug; FACS; High throughput; Leukemia; Screen; Stem cell
    DOI:  https://doi.org/10.21769/BioProtoc.4353
  2. World J Stem Cells. 2022 Feb 26. 14(2): 146-162
    Abnormal lipid synthesis as a therapeutic target for cancer stem cells.
    Si-Yu Wang, Qin-Chao Hu, Tong Wu, Juan Xia, Xiao-An Tao, Bin Cheng.
      Cancer stem cells (CSCs) comprise a subpopulation of cancer cells with stem cell properties, which exhibit the characteristics of high tumorigenicity, self-renewal, and tumor initiation and are associated with the occurrence, metastasis, therapy resistance, and relapse of cancer. Compared with differentiated cells, CSCs have unique metabolic characteristics, and metabolic reprogramming contributes to the self-renewal and maintenance of stem cells. It has been reported that CSCs are highly dependent on lipid metabolism to maintain stemness and satisfy the requirements of biosynthesis and energy metabolism. In this review, we demonstrate that lipid anabolism alterations promote the survival of CSCs, including de novo lipogenesis, lipid desaturation, and cholesterol synthesis. In addition, we also emphasize the molecular mechanism underlying the relationship between lipid synthesis and stem cell survival, the signal trans-duction pathways involved, and the application prospect of lipid synthesis reprogramming in CSC therapy. It is demonstrated that the dependence on lipid synthesis makes targeting of lipid synthesis metabolism a promising therapeutic strategy for eliminating CSCs. Targeting key molecules in lipid synthesis will play an important role in anti-CSC therapy.
    Keywords:  Anti-cancer therapy; Cancer stem cells; Lipid anabolism; Lipid synthesis; Stem cell survival
    DOI:  https://doi.org/10.4252/wjsc.v14.i2.146
  3. Mol Cell Biochem. 2022 Apr 22.
    Energetic metabolic reprogramming in Jurkat DFF40-deficient cancer cells.
    Merve Kulbay, Bruno Johnson, Guillaume Ricaud, Marie-Noëlle Séguin-Grignon, Jacques Bernier.
      DNA fragmentation factor 40 (DFF40), or the caspase-activated DNase (CAD), is an endonuclease specific for double-stranded DNA. Alterations in its function and expression have been linked to apoptosis resistance, a mechanism likely used by cancer cells. However, how the DFF40-related apoptosis resistance pathway occurs remains unclear. Here, we sought to determine if DFF40 expression could be linked to cell metabolism through the regulation of mitochondrial integrity and function. We demonstrated that DFF40-deficient cells are more resistant to staurosporine and tributyltin (TBT)-induced apoptosis, and express higher levels of Mcl-1 at basal state. Treatment with TBT induces higher Bcl-2 and caspase-9 mRNA transcripts in DFF40 KO Jurkat cells, as well as enhanced Bcl-2 phosphorylation. A loss of DFF40 expression induces a higher mitochondrial mass, mtDNA copy number, mitochondrial membrane potential, and glycolysis rates in resting T cells. DFF40-deficient cells exhibit the Warburg effect phenotype, where they rely significantly more on glycolysis than oxidative phosphorylation and have a higher proliferative state, demonstrated by a higher Ki-67 transcription factor expression and AKT phosphorylation. Finally, we demonstrated with cell fractioning that DFF40 can translocate to the mitochondria following apoptosis induction. Our study reveals that DFF40 may act as a regulator of mitochondria during cell death and its loss could compromise mitochondrial integrity and cause an energetic reprogramming in pathologies such as cancer.
    Keywords:  Apoptosis; Cancer; Cell proliferation; DFF40; DNA; Energetic metabolism; Mitochondria; Reprogramming; Warburg effect
    DOI:  https://doi.org/10.1007/s11010-022-04433-0
  4. Pol Merkur Lekarski. 2022 Apr 19. 50(296): 145-147
    [Anti-cancer properties of dichloroacetate].
    Małgorzata Latocha, Luiza Żyrek.
      One of the hallmarks of cancer cells is aerobic glycolysis (the Warburg effect). The effect of dichloroacetate (DCA) is to switch glucose metabolism (cellular respiration) to a more efficient process involving oxygen, reduce the production of lactic acid, activate the respiratory chain, change the potential of the mitochondrial membrane, and release pro-apoptotic mediators (cytochrome c and AIF) into the cytosol. As a result, the control over the mutated cells is improved, their sensitivity to various drugs or radiotherapy and their sensitivity to apoptosis increase. In the study the review of data on the mechanism of action of DCA on neoplastic cells was performed to indicate the side effects associated with the possible introduction of this compound to cancer therapy.
    Keywords:  cancer; dichloroacetate
  5. Eur J Cell Biol. 2022 Apr 13. pii: S0171-9335(22)00028-0. [Epub ahead of print]101(3): 151225
    Mitochondrial and metabolic alterations in cancer cells.
    Jacopo Di Gregorio, Sabrina Petricca, Roberto Iorio, Elena Toniato, Vincenzo Flati.
      Metabolic alterations have been observed in many cancer types. The deregulated metabolism has thus become an emerging hallmark of the disease, where the metabolism is frequently rewired to aerobic glycolysis. This has led to the concept of "metabolic reprogramming", which has therefore been extensively studied. Over the years, it has been characterized the enhancement of aerobic glycolysis, where key mutations in some of the enzymes of the TCA cycle, and the increased glucose uptake, are used by cancer cells to achieve a "metabolic phenotype" useful to gain a proliferation advantage. Many studies have highlighted in detail the signaling pathways and the molecular mechanisms responsible for the glycolytic switch. However, glycolysis is not the only metabolic process that cancer cells rely on. Oxidative Phosphorylation (OXPHOS), gluconeogenesis or the beta-oxidation of fatty acids (FAO) may be involved in the development and progression of several tumors. In some cases, these metabolisms are even more crucial than aerobic glycolysis for the tumor survival. This review will focus on the contribution of these alterations of metabolism to the development and survival of cancers. We will also analyze the molecular mechanisms by which the balance between these metabolic processes may be regulated, as well as some of the therapeutical approaches that can derive from their study.
    Keywords:  Amino acids; Cancer; Fatty acids; Metabolism; Mitochondria; OXPHOS
    DOI:  https://doi.org/10.1016/j.ejcb.2022.151225
  6. Cancers (Basel). 2022 Apr 07. pii: 1862. [Epub ahead of print]14(8):
    The Entanglement between Mitochondrial DNA and Tumor Metastasis.
    Qiwei Wu, Hsiang-I Tsai, Haitao Zhu, Dongqing Wang.
      Mitochondrial DNA, the genetic material in mitochondria, encodes essential oxidative phosphorylation proteins and plays an important role in mitochondrial respiration and energy transfer. With the development of genome sequencing and the emergence of novel in vivo modeling techniques, the role of mtDNA in cancer biology is gaining more attention. Abnormalities of mtDNA result in not only mitochondrial dysfunction of the the cancer cells and malignant behaviors, but regulation of the tumor microenvironment, which becomes more aggressive. Here, we review the recent progress in the regulation of cancer metastasis using mtDNA and the underlying mechanisms, which may identify opportunities for finding novel cancer prediction and therapeutic targets.
    Keywords:  immune escape; metastasis; mitochondrial DNA; tumor progression
    DOI:  https://doi.org/10.3390/cancers14081862
  7. Cell Metab. 2022 Apr 18. pii: S1550-4131(22)00127-9. [Epub ahead of print]
    The mitochondrial pyruvate carrier regulates memory T cell differentiation and antitumor function.
    Mathias Wenes, Alison Jaccard, Tania Wyss, Noelia Maldonado-Pérez, Shao Thing Teoh, Anouk Lepez, Fabrice Renaud, Fabien Franco, Patrice Waridel, Céline Yacoub Maroun, Benjamin Tschumi, Nina Dumauthioz, Lianjun Zhang, Alena Donda, Francisco Martín, Denis Migliorini, Sophia Y Lunt, Ping-Chih Ho, Pedro Romero.
      Glycolysis, including both lactate fermentation and pyruvate oxidation, orchestrates CD8+ T cell differentiation. However, how mitochondrial pyruvate metabolism and uptake controlled by the mitochondrial pyruvate carrier (MPC) impact T cell function and fate remains elusive. We found that genetic deletion of MPC drives CD8+ T cell differentiation toward a memory phenotype. Metabolic flexibility induced by MPC inhibition facilitated acetyl-coenzyme-A production by glutamine and fatty acid oxidation that results in enhanced histone acetylation and chromatin accessibility on pro-memory genes. However, in the tumor microenvironment, MPC is essential for sustaining lactate oxidation to support CD8+ T cell antitumor function. We further revealed that chimeric antigen receptor (CAR) T cell manufacturing with an MPC inhibitor imprinted a memory phenotype and demonstrated that infusing MPC inhibitor-conditioned CAR T cells resulted in superior and long-lasting antitumor activity. Altogether, we uncover that mitochondrial pyruvate uptake instructs metabolic flexibility for guiding T cell differentiation and antitumor responses.
    Keywords:  T cell memory; chimeric antigen receptor T cell therapy; immunometabolism; mitochondrial pyruvate carrier; tumor-infiltrating lymphocyte metabolism
    DOI:  https://doi.org/10.1016/j.cmet.2022.03.013
  8. Biosci Rep. 2022 Apr 29. pii: BSR20211812. [Epub ahead of print]42(4):
    The paradigm of drug resistance in cancer: an epigenetic perspective.
    Swagata Adhikari, Apoorva Bhattacharya, Santanu Adhikary, Vipin Singh, Shrikanth S Gadad, Siddhartha Roy, Chandrima Das.
      Innate and acquired resistance towards the conventional therapeutic regimen imposes a significant challenge for the successful management of cancer for decades. In patients with advanced carcinomas, acquisition of drug resistance often leads to tumor recurrence and poor prognosis after the first therapeutic cycle. In this context, cancer stem cells (CSCs) are considered as the prime drivers of therapy resistance in cancer due to their 'non-targetable' nature. Drug resistance in cancer is immensely influenced by different properties of CSCs such as epithelial-to-mesenchymal transition (EMT), a profound expression of drug efflux pump genes, detoxification genes, quiescence, and evasion of apoptosis, has been highlighted in this review article. The crucial epigenetic alterations that are intricately associated with regulating different mechanisms of drug resistance, have been discussed thoroughly. Additionally, special attention is drawn towards the epigenetic mechanisms behind the interaction between the cancer cells and their microenvironment which assists in tumor progression and therapy resistance. Finally, we have provided a cumulative overview of the alternative treatment strategies and epigenome-modifying therapies that show the potential of sensitizing the resistant cells towards the conventional treatment strategies. Thus, this review summarizes the epigenetic and molecular background behind therapy resistance, the prime hindrance of present day anti-cancer therapies, and provides an account of the novel complementary epi-drug-based therapeutic strategies to combat drug resistance.
    Keywords:  Cancer stem cells; cancer; drug resistance; epigenetics
    DOI:  https://doi.org/10.1042/BSR20211812
  9. Biomolecules. 2022 Apr 14. pii: 580. [Epub ahead of print]12(4):
    Effects of Glucose Metabolism, Lipid Metabolism, and Glutamine Metabolism on Tumor Microenvironment and Clinical Implications.
    Longfei Zhu, Xuanyu Zhu, Yan Wu.
      In recent years, an increasingly more in depth understanding of tumor metabolism in tumorigenesis, tumor growth, metastasis, and prognosis has been achieved. The broad heterogeneity in tumor tissue is the critical factor affecting the outcome of tumor treatment. Metabolic heterogeneity is not only found in tumor cells but also in their surrounding immune and stromal cells; for example, many suppressor cells, such as tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and tumor-associated T-lymphocytes. Abnormalities in metabolism often lead to short survival or resistance to antitumor therapy, e.g., chemotherapy, radiotherapy, targeted therapy, and immunotherapy. Using the metabolic characteristics of the tumor microenvironment to identify and treat cancer has become a great research hotspot. This review systematically addresses the impacts of metabolism on tumor cells and effector cells and represents recent research advances of metabolic effects on other cells in the tumor microenvironment. Finally, we introduce some applications of metabolic features in clinical oncology.
    Keywords:  fatty acid metabolism; glutaminolysis; glycolysis; immunotherapy; metabolism; tumor microenvironment
    DOI:  https://doi.org/10.3390/biom12040580
  10. Front Immunol. 2022 ;13 873834
    Impact of Drp1-Mediated Mitochondrial Dynamics on T Cell Immune Modulation.
    Jun Song, Xiaofang Yi, Ruolin Gao, Li Sun, Zhixuan Wu, Shuling Zhang, Letian Huang, Chengbo Han, Jietao Ma.
      In recent years, various breakthroughs have been made in tumor immunotherapy that have contributed to prolonging the survival of tumor patients. However, only a subset of patients respond to immunotherapy, which limits its use. One reason for this is that the tumor microenvironment (TME) hinders the migration and infiltration of T cells and affects their continuous functioning, resulting in an exhausted phenotype. Therefore, clarifying the mechanism by which T cells become exhausted is of significance for improving the efficacy of immunotherapy. Several recent studies have shown that mitochondrial dynamics play an important role in the immune surveillance function of T cells. Dynamin-related protein 1 (Drp1) is a key protein that mediates mitochondrial fission and maintains the mitochondrial dynamic network. Drp1 regulates various activities of T cells in vivo by mediating the activation of a series of pathways. In addition, abnormal mitochondrial dynamics were observed in exhausted T cells in the TME. As a potential target for immunotherapy, in this review, we describe in detail how Drp1 regulates various physiological functions of T cells and induces changes in mitochondrial dynamics in the TME, providing a theoretical basis for further research.
    Keywords:  T cell exhaustion; dynamin-related protein 1; immunotherapy; mitochondrial dynamics; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2022.873834
  11. Acta Naturae. 2022 Jan-Mar;14(1):14(1): 4-13
    Fifty Years of Research on Protonophores: Mitochondrial Uncoupling As a Basis for Therapeutic Action.
    E A Kotova, Y N Antonenko.
      Protonophores are compounds capable of electrogenic transport of protons across membranes. Protonophores have been intensively studied over the past 50 years owing to their ability to uncouple oxidation and phosphorylation in mitochondria and chloroplasts. The action mechanism of classical uncouplers, such as DNP and CCCP, in mitochondria is believed to be related to their protonophoric activity; i.e., their ability to transfer protons across the lipid part of the mitochondrial membrane. Given the recently revealed deviations in the correlation between the protonophoric activity of some uncouplers and their ability to stimulate mitochondrial respiration, this review addresses the involvement of some proteins of the inner mitochondrial membrane, such as the ATP/ADP antiporter, dicarboxylate carrier, and ATPase, in the uncoupling process. However, these deviations do not contradict the Mitchell theory but point to a more complex nature of the interaction of DNP, CCCP, and other uncouplers with mitochondrial membranes. Therefore, a detailed investigation of the action mechanism of uncouplers is required for a more successful pharmacological use, including their antibacterial, antiviral, anticancer, as well as cardio-, neuro-, and nephroprotective effects.
    Keywords:  bioenergetics; mitochondria; proton transport; uncouplers of oxidative phosphorylation
    DOI:  https://doi.org/10.32607/actanaturae.11610
  12. Science. 2022 Apr 22. 376(6591): 336
    Fight mutant cancer cells by … making more mutations?
    Jocelyn Kaiser.
      Chemotherapies that induce new DNA errors may help unleash the immune system on tumors.
    DOI:  https://doi.org/10.1126/science.abq6111
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