bims-almceb 2021-08-29 papers

bims-almceb

Biomed News

on Acute Leukemia Metabolism and Cell Biology

Issue of 2021–08–29
thirteen papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul

Insights on Metabolic Reprogramming and Its Therapeutic Potential in Acute Leukemia.
Protein networks linking Warburg and reverse Warburg effects to cancer cell metabolism.
Lipid metabolism and mitochondria: Cross talk in cancer.
Mitochondrial Uncoupling Proteins (UCP1-UCP3) and Adenine Nucleotide Translocase (ANT1) Enhance the Protonophoric Action of 2,4-Dinitrophenol in Mitochondria and Planar Bilayer Membranes.
Analyzing and disrupting leukemic stem cell adhesion to bone-marrow stromal cells by single molecule tracking nanoscopy.
Efficacy of a combination therapy targeting CDK4/6 and autophagy in a mouse xenograft model of t(8;21) acute myeloid leukemia.
NEI-01-induced arginine deprivation has potent activity against acute myeloid leukemia cells both in vitro and in vivo.
Dysregulated cholesterol homeostasis results in resistance to ferroptosis increasing tumorigenicity and metastasis in cancer.
Mitochondrial Carriers and Substrates Transport Network: A Lesson from Saccharomyces cerevisiae.
Decoupling Lineage-Associated Genes in Acute Myeloid Leukemia Reveals Inflammatory and Metabolic Signatures Associated With Outcomes.
The Effect of Oxygen and Micronutrient Composition of Cell Growth Media on Cancer Cell Bioenergetics and Mitochondrial Networks.
Can the New and Old Drugs Exert an Immunomodulatory Effect in Acute Myeloid Leukemia?
The mitochondrial coenzyme Q junction and complex III: biochemistry and pathophysiology.

Int J Mol Sci. 2021 Aug 14. pii: 8738. [Epub ahead of print]22(16):

Insights on Metabolic Reprogramming and Its Therapeutic Potential in Acute Leukemia.

Ludovica Di Martino, Valeria Tosello, Edoardo Peroni, Erich Piovan.

  Acute leukemias, classified as acute myeloid leukemia and acute lymphoblastic leukemia, represent the most prevalent hematologic tumors in adolescent and young adults. In recent years, new challenges have emerged in order to improve the clinical effectiveness of therapies already in use and reduce their side effects. In particular, in this scenario, metabolic reprogramming plays a key role in tumorigenesis and prognosis, and it contributes to the treatment outcome of acute leukemia. This review summarizes the latest findings regarding the most relevant metabolic pathways contributing to the continuous growth, redox homeostasis, and drug resistance of leukemia cells. We describe the main metabolic deregulations in acute leukemia and evidence vulnerabilities that could be exploited for targeted therapy.

Keywords:  acute leukemia; metabolism; targeted therapy

DOI:  https://doi.org/10.3390/ijms22168738
Biofactors. 2021 Aug 28.

Protein networks linking Warburg and reverse Warburg effects to cancer cell metabolism.

Dina Johar, Ahmed O Elmehrath, Rania M Khalil, Mostafa H Elberry, Samy Zaky, Samy A Shalabi, Larry H Bernstein.

  It was 80 years after the Otto Warburg discovery of aerobic glycolysis, a major hallmark in the understanding of cancer. The Warburg effect is the preference of cancer cell for glycolysis that produces lactate even when sufficient oxygen is provided. "reverse Warburg effect" refers to the interstitial tissue communications with adjacent epithelium, that in the process of carcinogenesis, is needed to be explored. Among these cell-cell communications, the contact between epithelial cells; between epithelial cells and matrix; and between fibroblasts and inflammatory cells in the underlying matrix. Cancer involves dysregulation of Warburg and reverse Warburg cellular metabolic pathways. How these gene and protein-based regulatory mechanisms have functioned has been the basis for this review. The importance of the Warburg in oxidative phosphorylation suppression, with increased glycolysis in cancer growth and proliferation is emphasized. Studies that are directed at pathways that would be expected to shift cell metabolism to an increased oxidation and to a decrease in glycolysis are emphasized. Key enzymes required for oxidative phosphorylation, and affect the inhibition of fatty acid metabolism and glutamine dependence are conferred. The findings are of special interest to cancer pharmacotherapy. Studies described in this review are concerned with the effects of therapeutic modalities that are intimately related to the Warburg effect. These interactions described may be helpful as adjuvant therapy in controlling the process of proliferation and metastasis.

Keywords:  Warburg; aerobic; anaerobic; cancer; glycolysis; metastasis; proliferation; tumorigenesis

DOI:  https://doi.org/10.1002/biof.1768
Curr Drug Targets. 2021 Aug 24.

Lipid metabolism and mitochondria: Cross talk in cancer.

Anubhav Srivastava, Pransu Srivastava, Shashank Mathur, Sabiya Abbas, Neeraj Rai, Swasti Tiwari, Meenakshi Tiwari, Lokendra Sharma.

  Metabolic reprogramming is considered a major event in cancer initiation, progression and metastasis. The metabolic signature of cancer cells includes alterations in glycolysis, mitochondrial respiration, fatty acid/lipid and amino acid metabolism. Being at a junction of various metabolic pathways, mitochondria play a key role in fueling cancer growth through regulating bioenergetics, metabolism and cell death. Increasing evidence suggests that alteration in lipid metabolism is a common feature of metastatic progression, including fatty acid synthesis as well as fatty acid oxidation. However, the interplay between lipid metabolism and mitochondria in carcinogenesis remains obscure. The present review focuses on key lipid metabolic pathways associated with mitochondrial regulation that drive cancer phenotype and metastasis. We also review potential targets of lipid metabolism and mitochondria to improve the therapeutic regime in cancer patients. This review aims to improve our current understanding of the intricate relation of lipids with mitochondria and provides insights into new therapeutic approaches.

Keywords:  Apoptosis; Bioenergetics; Cancer; Cardiolipin; Chemo-therapeutics; Drug Targets; Fatty acid oxidation; Lipid metabolism; Metastasis; Mitochondria

DOI:  https://doi.org/10.2174/1389450122666210824144907
Biomolecules. 2021 Aug 09. pii: 1178. [Epub ahead of print]11(8):

Mitochondrial Uncoupling Proteins (UCP1-UCP3) and Adenine Nucleotide Translocase (ANT1) Enhance the Protonophoric Action of 2,4-Dinitrophenol in Mitochondria and Planar Bilayer Membranes.

Kristina Žuna, Olga Jovanović, Ljudmila S Khailova, Sanja Škulj, Zlatko Brkljača, Jürgen Kreiter, Elena A Kotova, Mario Vazdar, Yuri N Antonenko, Elena E Pohl.

  2,4-Dinitrophenol (DNP) is a classic uncoupler of oxidative phosphorylation in mitochondria which is still used in "diet pills", despite its high toxicity and lack of antidotes. DNP increases the proton current through pure lipid membranes, similar to other chemical uncouplers. However, the molecular mechanism of its action in the mitochondria is far from being understood. The sensitivity of DNP's uncoupling action in mitochondria to carboxyatractyloside, a specific inhibitor of adenine nucleotide translocase (ANT), suggests the involvement of ANT and probably other mitochondrial proton-transporting proteins in the DNP's protonophoric activity. To test this hypothesis, we investigated the contribution of recombinant ANT1 and the uncoupling proteins UCP1-UCP3 to DNP-mediated proton leakage using the well-defined model of planar bilayer lipid membranes. All four proteins significantly enhanced the protonophoric effect of DNP. Notably, only long-chain free fatty acids were previously shown to be co-factors of UCPs and ANT1. Using site-directed mutagenesis and molecular dynamics simulations, we showed that arginine 79 of ANT1 is crucial for the DNP-mediated increase of membrane conductance, implying that this amino acid participates in DNP binding to ANT1.

Keywords:  artificial membranes; membrane potential; mitochondrial uncoupler; molecular dynamics simulations; proton conductance; protonophore

DOI:  https://doi.org/10.3390/biom11081178
J Cell Sci. 2021 Aug 26. pii: jcs.258736. [Epub ahead of print]

Analyzing and disrupting leukemic stem cell adhesion to bone-marrow stromal cells by single molecule tracking nanoscopy.

Oksana Gorshkova, Jessica Cappaï, Loriane Maillot, Arnauld Sergé.

  Leukemic stem cells (LSC) adhere to bone niches by adhesion molecules. These interactions, deeply reorganized in tumors, contribute to LSC resistance and leukemia relapse. However, LSC adhesion mechanisms and potential therapeutic disruption using blocking antibodies remain largely unknown. Junctional adhesion molecule JAM-C over-expression by LSC correlates with increased leukemia severity, constituting a putative therapeutic target. Here, we took advantage of nanoscopy ability to detect single molecules with nanometric accuracy to characterize JAM dynamics at leuko-stromal contacts. Videonanoscopy trajectories were reconstructed using our dedicated Multi-Target Tracing algorithm, pipelined with dual-color analyses (MTT2col). JAM-C expressed by LSCs engaged transient interactions with JAM-B expressed by stromal cells. JAM recruitment and colocalization at cell contacts were proportional to JAM-C level and reduced by a blocking anti-JAM-C antibody. MTT2col revealed at single-molecule resolution the modalities of blocking antibodies to destabilize LSC binding to their niches, opening opportunities for disrupting LSC resistance mechanisms.

Keywords:  Adhesion; Leukemic stem cell; Nanoscopy; Ssingle molecule tracking; Super-resolution

DOI:  https://doi.org/10.1242/jcs.258736
Biochem Biophys Rep. 2021 Sep;27 101099

Efficacy of a combination therapy targeting CDK4/6 and autophagy in a mouse xenograft model of t(8;21) acute myeloid leukemia.

Hidemasa Matsuo, Kana Nakatani, Yutarou Harata, Moe Higashitani, Yuri Ito, Aina Inagami, Mina Noura, Tatsutoshi Nakahata, Souichi Adachi.

  One of the most frequent cytogenetic abnormalities in acute myeloid leukemia (AML) is t(8;21). Although patients with t(8;21) AML have a more favorable prognosis than other cytogenetic subgroups, relapse is still common and novel therapeutic approaches are needed. A recent study showed that t(8;21) AML is characterized by CCND2 deregulation and that co-inhibition of CDK4/6 and autophagy induces apoptosis in t(8;21) AML cells. In this study, we examined the in vivo effects of co-inhibiting CDK4/6 and autophagy. We used a mouse model in which t(8;21)-positive Kasumi-1 cells were subcutaneously inoculated into NOD/Shi-scid IL2Rgnull mice. The mice were treated with the autophagy inhibitor chloroquine (CQ), a CDK4/6 inhibitor (either abemaciclib or palbociclib), or a CDK4/6 inhibitor plus CQ. After 20 days of treatment, tumor volume was measured, and immunostaining and transmission electron microscopy observations were performed. There was no change in tumor growth in CQ-treated mice. However, mice treated with a CDK4/6 inhibitor plus CQ had significantly less tumor growth than mice treated with a CDK4/6 inhibitor alone. CDK4/6 inhibitor treatment increased the formation of autophagosomes. The number of single-strand DNA-positive (apoptotic) cells was significantly higher in the tumors of mice treated with a CDK4/6 inhibitor plus CQ than in mice treated with either CQ or a CDK4/6 inhibitor. These results show that CDK4/6 inhibition induces autophagy, and that co-inhibition of CDK4/6 and autophagy induces apoptosis in t(8;21) AML cells in vivo. The results suggest that inhibiting CDK4/6 and autophagy could be a novel and promising therapeutic strategy in t(8;21) AML.

Keywords:  Apoptosis; Autophagy; CDK4/6; Leukemia; t(8;21)

DOI:  https://doi.org/10.1016/j.bbrep.2021.101099
Mol Cancer Ther. 2021 Aug 25. pii: molcanther.0120.2021. [Epub ahead of print]

NEI-01-induced arginine deprivation has potent activity against acute myeloid leukemia cells both in vitro and in vivo.

Yun-Chung Leung, Yijun Cai, Jeremy P H Chow, Yu-On Leung, Xiaoxu Lu, Chak-Ho Yuen, Wing Lun Lee, Ka-Chun Chau, Liz L Yang, Raymond M H Wong, Justin Y T Lam, Daniel T L Chow, Steven H K Chung, Sui-Yi Kwok.

Recent studies have revealed that targeting amino acid metabolic enzymes is a promising strategy in cancer therapy. Acute myeloid leukemia (AML) downregulates the expression of argininosuccinate synthase (ASS1), a recognized rate-limiting enzyme for arginine synthesis, and yet displays a critical dependence on extracellular arginine for survival and proliferation. This dependence on extracellular arginine, also known as arginine auxotrophy, suggests that arginine deprivation would be a treatment strategy for AML. NEI-01, a novel arginine-depleting enzyme, is capable of binding to serum albumin to extend its circulating half-life, leading to a potent anticancer activity. Here we reported the preclinical activity of NEI-01 in arginine auxotrophic AMLs. NEI-01 efficiently depleted arginine both in vitro and in vivo. NEI-01-induced arginine deprivation was cytotoxic to arginine auxotrophic AML cells through induction of cell cycle arrest and apoptosis. Furthermore, the potent anti-leukemia activities of NEI-01 were observed in three different types of mouse models including human cell line-derived xenograft (CDX), mouse cell line-derived homografts in syngeneic mice and patient-derived xenograft (PDX). This preclinical data provide strong evidence to support the potential use of NEI-01 as a therapeutic approach in AML treatment.

DOI: https://doi.org/10.1158/1535-7163.MCT-21-0120
Nat Commun. 2021 08 24. 12(1): 5103

Dysregulated cholesterol homeostasis results in resistance to ferroptosis increasing tumorigenicity and metastasis in cancer.

Wen Liu, Binita Chakraborty, Rachid Safi, Dmitri Kazmin, Ching-Yi Chang, Donald P McDonnell.

Hypercholesterolemia and dyslipidemia are associated with an increased risk for many cancer types and with poor outcomes in patients with established disease. Whereas the mechanisms by which this occurs are multifactorial we determine that chronic exposure of cells to 27-hydroxycholesterol (27HC), an abundant circulating cholesterol metabolite, selects for cells that exhibit increased cellular uptake and/or lipid biosynthesis. These cells exhibit substantially increased tumorigenic and metastatic capacity. Notably, the metabolic stress imposed upon cells by the accumulated lipids requires sustained expression of GPX4, a negative regulator of ferroptotic cell death. We show that resistance to ferroptosis is a feature of metastatic cells and further demonstrate that GPX4 knockdown attenuates the enhanced tumorigenic and metastatic activity of 27HC resistant cells. These findings highlight the general importance of ferroptosis in tumor growth and metastasis and suggest that dyslipidemia/hypercholesterolemia impacts cancer pathogenesis by selecting for cells that are resistant to ferroptotic cell death.

DOI: https://doi.org/10.1038/s41467-021-25354-4
Int J Mol Sci. 2021 Aug 07. pii: 8496. [Epub ahead of print]22(16):

Mitochondrial Carriers and Substrates Transport Network: A Lesson from Saccharomyces cerevisiae.

Alessandra Ferramosca, Vincenzo Zara.

  The yeast Saccharomyces cerevisiae is one of the most widely used model organisms for investigating various aspects of basic cellular functions that are conserved in human cells. This organism, as well as human cells, can modulate its metabolism in response to specific growth conditions, different environmental changes, and nutrient depletion. This adaptation results in a metabolic reprogramming of specific metabolic pathways. Mitochondrial carriers play a fundamental role in cellular metabolism, connecting mitochondrial with cytosolic reactions. By transporting substrates across the inner membrane of mitochondria, they contribute to many processes that are central to cellular function. The genome of Saccharomyces cerevisiae encodes 35 members of the mitochondrial carrier family, most of which have been functionally characterized. The aim of this review is to describe the role of the so far identified yeast mitochondrial carriers in cell metabolism, attempting to show the functional connections between substrates transport and specific metabolic pathways, such as oxidative phosphorylation, lipid metabolism, gluconeogenesis, and amino acids synthesis. Analysis of the literature reveals that these proteins transport substrates involved in the same metabolic pathway with a high degree of flexibility and coordination. The understanding of the role of mitochondrial carriers in yeast biology and metabolism could be useful for clarifying unexplored aspects related to the mitochondrial carrier network. Such knowledge will hopefully help in obtaining more insight into the molecular basis of human diseases.

Keywords:  Saccharomyces cerevisiae; metabolism; mitochondria; mitochondrial carrier; transport

DOI:  https://doi.org/10.3390/ijms22168496
Front Oncol. 2021 ;11 705627

Decoupling Lineage-Associated Genes in Acute Myeloid Leukemia Reveals Inflammatory and Metabolic Signatures Associated With Outcomes.

Hussein A Abbas, Vakul Mohanty, Ruiping Wang, Yuefan Huang, Shaoheng Liang, Feng Wang, Jianhua Zhang, Yihua Qiu, Chenyue W Hu, Amina A Qutub, Monique Dail, Christopher R Bolen, Naval Daver, Marina Konopleva, Andrew Futreal, Ken Chen, Linghua Wang, Steven M Kornblau.

  Acute myeloid leukemia (AML) is a heterogeneous disease with variable responses to therapy. Cytogenetic and genomic features are used to classify AML patients into prognostic and treatment groups. However, these molecular characteristics harbor significant patient-to-patient variability and do not fully account for AML heterogeneity. RNA-based classifications have also been applied in AML as an alternative approach, but transcriptomic grouping is strongly associated with AML morphologic lineages. We used a training cohort of newly diagnosed AML patients and conducted unsupervised RNA-based classification after excluding lineage-associated genes. We identified three AML patient groups that have distinct biological pathways associated with outcomes. Enrichment of inflammatory pathways and downregulation of HOX pathways were associated with improved outcomes, and this was validated in 2 independent cohorts. We also identified a group of AML patients who harbored high metabolic and mTOR pathway activity, and this was associated with worse clinical outcomes. Using a comprehensive reverse phase protein array, we identified higher mTOR protein expression in the highly metabolic group. We also identified a positive correlation between degree of resistance to venetoclax and mTOR activation in myeloid and lymphoid cell lines. Our approach of integrating RNA, protein, and genomic data uncovered lineage-independent AML patient groups that share biologic mechanisms and can inform outcomes independent of commonly used clinical and demographic variables; these groups could be used to guide therapeutic strategies.

Keywords:  acute myeloid leukemia; inflammation; lineage; metabolism; multiplatform analysis

DOI:  https://doi.org/10.3389/fonc.2021.705627
Biomolecules. 2021 Aug 09. pii: 1177. [Epub ahead of print]11(8):

The Effect of Oxygen and Micronutrient Composition of Cell Growth Media on Cancer Cell Bioenergetics and Mitochondrial Networks.

Fereshteh Moradi, Christopher Moffatt, Jeffrey A Stuart.

  Cancer cell culture is routinely performed under superphysiologic O2 levels and in media such as Dulbecco's Modified Eagle Medium (DMEM) with nutrient composition dissimilar to mammalian extracellular fluid. Recently developed cell culture media (e.g., Plasmax, Human Plasma-Like Medium (HPLM)), which are modeled on the metabolite composition of human blood plasma, have been shown to shift key cellular activities in several cancer cell lines. Similar effects have been reported with respect to O2 levels in cell culture. Given these observations, we investigated how media composition and O2 levels affect cellular energy metabolism and mitochondria network structure in MCF7, SaOS2, LNCaP, and Huh7 cells. Cells were cultured in physiologic (5%) or standard (18%) O2 levels, and in physiologic (Plasmax) or standard cell culture media (DMEM). We show that both O2 levels and media composition significantly affect mitochondrial abundance and network structure, concomitantly with changes in cellular bioenergetics. Extracellular acidification rate (ECAR), a proxy for glycolytic activity, was generally higher in cells cultured in DMEM while oxygen consumption rates (OCR) were lower. This effect of media on energy metabolism is an important consideration for the study of cancer drugs that target aspects of energy metabolism, including lactate dehydrogenase activity.

Keywords:  cell culture; glycolysis; metabolism; mitochondria; mitochondrial networks; oxidative phosphorylation

DOI:  https://doi.org/10.3390/biom11081177
Cancers (Basel). 2021 Aug 16. pii: 4121. [Epub ahead of print]13(16):

Can the New and Old Drugs Exert an Immunomodulatory Effect in Acute Myeloid Leukemia?

Francesco Tarantini, Cosimo Cumbo, Luisa Anelli, Antonella Zagaria, Giorgina Specchia, Pellegrino Musto, Francesco Albano.

  Acute myeloid leukemia (AML) is considered an immune-suppressive neoplasm capable of evading immune surveillance through cellular and environmental players. Increasing knowledge of the immune system (IS) status at diagnosis seems to suggest ever more attention of the crosstalk between the leukemic clone and its immunologic counterpart. During the last years, the advent of novel immunotherapeutic strategies has revealed the importance of immune dysregulation and suppression for leukemia fitness. Considering all these premises, we reviewed the "off-target" effects on the IS of different drugs used in the treatment of AML, focusing on the main advantages of this interaction. The data reported support the idea that a successful therapeutic strategy should consider tailored approaches for performing leukemia eradication by both direct blasts killing and the engagement of the IS.

Keywords:  AML treatment; acute myeloid leukemia; immunomodulation

DOI:  https://doi.org/10.3390/cancers13164121
FEBS J. 2021 Aug 24.

The mitochondrial coenzyme Q junction and complex III: biochemistry and pathophysiology.

Rishi Banerjee, Janne Purhonen, Jukka Kallijärvi.

  Coenzyme Q (CoQ, ubiquinone) is the electron-carrying lipid in the mitochondrial electron transport system (ETS). In mammals, it serves as the electron acceptor for nine mitochondrial inner membrane dehydrogenases. These include the NADH-dehydrogenase (complex I, CI) and succinate dehydrogenase (complex II, CII) but also several others that are often omitted in the context of respiratory enzymes: dihydroorotate dehydrogenase, choline dehydrogenase, electron-transferring flavoprotein dehydrogenase, mitochondrial glycerol-3-phosphate dehydrogenase, proline dehydrogenases 1 and 2, and sulfide:quinone oxidoreductase. The metabolic pathways these enzymes are involved in range from amino acid and fatty acid oxidation to nucleotide biosynthesis, methylation, and hydrogen sulfide detoxification, among many others. The CoQ-linked metabolism depends on CoQ re-oxidation by the mitochondrial complex III (cytochrome bc1 complex, CIII). However, the literature is surprisingly limited as for the role of the CoQ-linked metabolism in the pathogenesis of human diseases of oxidative phosphorylation (OXPHOS), in which the CoQ homeostasis is directly or indirectly affected. In this review, we give an introduction to CIII function, and an overview of the pathological consequences of CIII dysfunction in humans and mice and of the CoQ-dependent metabolic processes potentially affected in these pathological states. Finally, we discuss some experimental tools to dissect the various aspects of compromised CoQ oxidation.

Keywords:  coenzyme Q; complex III; mitochondrial disease; oxidative phosphorylation; ubiquinone

DOI:  https://doi.org/10.1111/febs.16164