bims-almceb 2021-04-04 papers

bims-almceb

Biomed News

on Acute Leukemia Metabolism and Cell Biology

Issue of 2021‒04‒04
twenty papers selected by
Camila Kehl Dias
Federal University of Rio Grande do Sul

Opa1 relies on cristae preservation and ATP synthase to curtail reactive oxygen species accumulation in mitochondria.
Stem Cell Metabolism and Diet.
Energy Metabolism in IDH1 Wild-Type and IDH1-Mutated Glioblastoma Stem Cells: A Novel Target for Therapy?
Outcomes of Adults With Relapsed/Refractory Acute Myeloid Leukemia Treated With Venetoclax Plus Hypomethylating Agents at a Comprehensive Cancer Center.
The Interactome between Metabolism and Gene Mutations in Myeloid Malignancies.
Playing the Whack-A-Mole Game: ERK5 Activation Emerges Among the Resistance Mechanisms to RAF-MEK1/2-ERK1/2- Targeted Therapy.
Warburg's Ghost-Cancer's Self-Sustaining Phenotype: The Aberrant Carbon Flux in Cholesterol-Enriched Tumor Mitochondria via Deregulated Cholesterogenesis.
Power of an Organic Electron Acceptor in Modulation of Intracellular Mitochondrial Reactive Oxygen Species: Inducing JNK- and Caspase-Dependent Apoptosis of Cancer Cells.
European Myeloma Network perspective on CAR T-Cell therapies for multiple myeloma.
Cellular Immunotherapy Targeting Cancer Stem Cells: Preclinical Evidence and Clinical Perspective.
Mitochondrial Fuel Dependence on Glutamine Drives Chemo-Resistance in the Cancer Stem Cells of Hepatocellular Carcinoma.
MITF induces escape from innate immunity in melanoma.
Immune evasion by cancer stem cells.
The Importance of Mitochondrial Pyruvate Carrier in Cancer Cell Metabolism and Tumorigenesis.
Mutational and functional genetics mapping of chemotherapy resistance mechanisms in relapsed acute lymphoblastic leukemia.
Overcoming Glucocorticoid Resistance in Acute Lymphoblastic Leukemia: Repurposed Drugs Can Improve the Protocol.
ANT1 Activation and Inhibition Patterns Support the Fatty Acid Cycling Mechanism for Proton Transport.
The Role of Cytokines and Chemokines in Shaping the Immune Microenvironment of Glioblastoma: Implications for Immunotherapy.
Reactive Oxygen Species Rewires Metabolic Activity in Acute Myeloid Leukemia.
The Mitochondrial Carnitine Acyl-carnitine Carrier (SLC25A20): Molecular Mechanisms of Transport, Role in Redox Sensing and Interaction with Drugs.

Redox Biol. 2021 Mar 19. pii: S2213-2317(21)00092-6. [Epub ahead of print]41 101944

Opa1 relies on cristae preservation and ATP synthase to curtail reactive oxygen species accumulation in mitochondria.

Rubén Quintana-Cabrera, Israel Manjarrés-Raza, Carlos Vicente-Gutiérrez, Mauro Corrado, Juan P Bolaños, Luca Scorrano.

  Reactive oxygen species (ROS) are a common product of active mitochondrial respiration carried in mitochondrial cristae, but whether cristae shape influences ROS levels is unclear. Here we report that the mitochondrial fusion and cristae shape protein Opa1 requires mitochondrial ATP synthase oligomers to reduce ROS accumulation. In cells fueled with galactose to force ATP production by mitochondria, cristae are enlarged, ATP synthase oligomers destabilized, and ROS accumulate. Opa1 prevents both cristae remodeling and ROS generation, without impinging on levels of mitochondrial antioxidant defense enzymes that are unaffected by Opa1 overexpression. Genetic and pharmacologic experiments indicate that Opa1 requires ATP synthase oligomerization and activity to reduce ROS levels upon a blockage of the electron transport chain. Our results indicate that the converging effect of Opa1 and mitochondrial ATP synthase on mitochondrial ultrastructure regulate ROS abundance to sustain cell viability.

Keywords:  Bioenergetics; F(1)F(O)-ATP synthase; Mitochondrial cristae; Opa1; ROS; Ultrastructure

DOI:  https://doi.org/10.1016/j.redox.2021.101944
Curr Stem Cell Rep. 2020 Dec;6(4): 119-125

Stem Cell Metabolism and Diet.

Marine Barthez, Zehan Song, Chih Ling Wang, Danica Chen.

  Purpose of Review: Diet has profound impacts on health and longevity. Evidence is emerging to suggest that diet impinges upon the metabolic pathways in tissue-specific stem cells to influence health and disease. Here, we review the similarities and differences in the metabolism of stem cells from several tissues, and highlight the mitochondrial metabolic checkpoint in stem cell maintenance and aging. We discuss how diet engages the nutrient sensing metabolic pathways and impacts stem cell maintenance. Finally, we explore the therapeutic implications of dietary and metabolic regulation of stem cells.Recent findings: Stem Cell transition from quiescence to proliferation is associated with a metabolic switch from glycolysis to mitochondrial OXPHOS and the mitochondrial metabolic checkpoint is critically controlled by the nutrient sensors SIRT2, SIRT3, and SIRT7 in hematopoietic stem cells. Intestine stem cell homeostasis during aging and in response to diet is critically dependent on fatty acid metabolism and ketone bodies and is influenced by the niche mediated by the nutrient sensor mTOR.
Summary: Nutrient sensing metabolic pathways critically regulate stem cell maintenance during aging and in response to diet. Elucidating the molecular mechanisms underlying dietary and metabolic regulation of stem cells provides novel insights for stem cell biology and may be targeted therapeutically to reverse stem cell aging and tissue degeneration.

Keywords:  SIRT2; SIRT3; SIRT7; calorie restriction; mTOR; stem cell metabolism

DOI:  https://doi.org/10.1007/s40778-020-00180-4
Cells. 2021 Mar 22. pii: 705. [Epub ahead of print]10(3):

Energy Metabolism in IDH1 Wild-Type and IDH1-Mutated Glioblastoma Stem Cells: A Novel Target for Therapy?

Cornelis J F van Noorden, Vashendriya V V Hira, Amber J van Dijck, Metka Novak, Barbara Breznik, Remco J Molenaar.

  Cancer is a redox disease. Low levels of reactive oxygen species (ROS) are beneficial for cells and have anti-cancer effects. ROS are produced in the mitochondria during ATP production by oxidative phosphorylation (OXPHOS). In the present review, we describe ATP production in primary brain tumors, glioblastoma, in relation to ROS production. Differentiated glioblastoma cells mainly use glycolysis for ATP production (aerobic glycolysis) without ROS production, whereas glioblastoma stem cells (GSCs) in hypoxic periarteriolar niches use OXPHOS for ATP and ROS production, which is modest because of the hypoxia and quiescence of GSCs. In a significant proportion of glioblastoma, isocitrate dehydrogenase 1 (IDH1) is mutated, causing metabolic rewiring, and all cancer cells use OXPHOS for ATP and ROS production. Systemic therapeutic inhibition of glycolysis is not an option as clinical trials have shown ineffectiveness or unwanted side effects. We argue that systemic therapeutic inhibition of OXPHOS is not an option either because the anti-cancer effects of ROS production in healthy cells is inhibited as well. Therefore, we advocate to remove GSCs out of their hypoxic niches by the inhibition of their binding to niches to enable their differentiation and thus increase their sensitivity to radiotherapy and/or chemotherapy.

Keywords:  IDH1-mutation; energy metabolism; glioblastoma stem cells

DOI:  https://doi.org/10.3390/cells10030705
Front Oncol. 2021 ;11 649209

Outcomes of Adults With Relapsed/Refractory Acute Myeloid Leukemia Treated With Venetoclax Plus Hypomethylating Agents at a Comprehensive Cancer Center.

Matthew E Tenold, Benjamin N Moskoff, David J Benjamin, Rasmus T Hoeg, Aaron S Rosenberg, Mehrdad Abedi, Joseph M Tuscano, Brian A Jonas.

  Relapsed/refractory acute myeloid leukemia (AML) is a devastating disease with a poor prognosis and represents a major unmet medical need. We report on a real-world academic center experience of treating 25 patients with relapsed/refractory AML using venetoclax in combination with decitabine or azacitidine, which is not otherwise widely evaluated in the current literature. Our patients come from a large, socioeconomically and geographically diverse area including the majority of Northern California. Most had ELN Adverse Risk (52%) or Intermediate Risk (44%) AML, and most had an ECOG Performance Status of 1 (64%). Over half (52%) had prior hypomethylating agent exposure, and 40% had Secondary AML. We observed an overall response rate of 52%, with eight patients (32%) achieving composite complete remission. Median overall survival was 5.5 months, and for patients achieving composite complete remission this was 21.6 months. One-year estimated overall survival was 38%. Three patients were able to proceed directly to stem cell transplant for consolidation, and all three were alive at last follow-up, ranging 13.8-24.0 months. We found venetoclax in combination with hypomethylating agents to be well tolerated and potentially efficacious in securing long-term remissions for patients with relapsed/refractory AML.

Keywords:  acute myeloid leukemia; hypomethylating agent; real-world data; relapsed/refractory; venetoclax (BCL-2 inhibitor)

DOI:  https://doi.org/10.3389/fonc.2021.649209
Int J Mol Sci. 2021 Mar 19. pii: 3135. [Epub ahead of print]22(6):

The Interactome between Metabolism and Gene Mutations in Myeloid Malignancies.

Carmelo Gurnari, Simona Pagliuca, Valeria Visconte.

  The study of metabolic deregulation in myeloid malignancies has led to the investigation of metabolic-targeted therapies considering that cells undergoing leukemic transformation have excessive energy demands for growth and proliferation. However, the most difficult challenge in agents targeting metabolism is to determine a window of therapeutic opportunities between normal and neoplastic cells, considering that all or most of the metabolic pathways important for cancer ontogeny may also regulate physiological cell functions. Targeted therapies have used the properties of leukemic cells to produce altered metabolic products when mutated. This is the case of IDH1/2 mutations generating the abnormal conversion of α-ketoglutarate (KG) to 2-hydroxyglutarate, an oncometabolite inhibiting KG-dependent enzymes, such as the TET family of genes (pivotal in characterizing leukemia cells either by mutations, e.g., TET2, or by altered expression, e.g., TET1/2/3). Additional observations derive from the high sensitivity of leukemic cells to oxidative phosphorylation and its amelioration using BCL-2 inhibitors (Venetoclax) or by disrupting the mitochondrial respiration. More recently, nicotinamide metabolism has been described to mediate resistance to Venetoclax in patients with acute myeloid leukemia. Herein, we will provide an overview of the latest research on the link between metabolic pathways interactome and leukemogenesis with a comprehensive analysis of the metabolic consequences of driver genetic lesions and exemplificative druggable pathways.

Keywords:  IDH1/2 mutations; TET2 mutations; myeloid malignancies; nicotinamide; venetoclax

DOI:  https://doi.org/10.3390/ijms22063135
Front Cell Dev Biol. 2021 ;9 647311

Playing the Whack-A-Mole Game: ERK5 Activation Emerges Among the Resistance Mechanisms to RAF-MEK1/2-ERK1/2- Targeted Therapy.

Alessandro Tubita, Ignazia Tusa, Elisabetta Rovida.

  Molecularly tailored therapies have opened a new era, chronic myeloid leukemia being the ideal example, in the treatment of cancer. However, available therapeutic options are still unsatisfactory in many types of cancer, and often fail due to the occurrence of resistance mechanisms. With regard to small-molecule compounds targeting the components of the Mitogen-Activated Protein Kinase (MAPK) cascade RAF-MEK1/2-ERK1/2, these drugs may result ineffective as a consequence of the activation of compensatory pro-survival/proliferative signals, including receptor tyrosine kinases, PI3K, as well as other components of the MAPK family such as TPL2/COT. The MAPK ERK5 has been identified as a key signaling molecule in the biology of several types of cancer. In this review, we report pieces of evidence regarding the activation of the MEK5-ERK5 pathway as a resistance mechanism to RAF-MEK1/2-ERK1/2 inhibitors. We also highlight the known and possible mechanisms underlying the cross-talks between the ERK1/2 and the ERK5 pathways, the characterization of which is of great importance to maximize, in the future, the impact of RAF-MEK1/2-ERK1/2 targeting. Finally, we emphasize the need of developing additional therapeutically relevant MEK5-ERK5 inhibitors to be used for combined treatments, thus preventing the onset of resistance to cancer therapies relying on RAF-MEK1/2-ERK1/2 inhibitors.

Keywords:  ERK1/2/5; MAPK; cancer; combined therapy; resistance mechanisms; targeted therapy

DOI:  https://doi.org/10.3389/fcell.2021.647311
Front Cell Dev Biol. 2021 ;9 626316

Warburg's Ghost-Cancer's Self-Sustaining Phenotype: The Aberrant Carbon Flux in Cholesterol-Enriched Tumor Mitochondria via Deregulated Cholesterogenesis.

Peter S Coleman, Risa A Parlo.

  Interpreting connections between the multiple networks of cell metabolism is indispensable for understanding how cells maintain homeostasis or transform into the decontrolled proliferation phenotype of cancer. Situated at a critical metabolic intersection, citrate, derived via glycolysis, serves as either a combustible fuel for aerobic mitochondrial bioenergetics or as a continuously replenished cytosolic carbon source for lipid biosynthesis, an essentially anaerobic process. Therein lies the paradox: under what conditions do cells control the metabolic route by which they process citrate? The Warburg effect exposes essentially the same dilemma-why do cancer cells, despite an abundance of oxygen needed for energy-generating mitochondrial respiration with citrate as fuel, avoid catabolizing mitochondrial citrate and instead rely upon accelerated glycolysis to support their energy requirements? This review details the genesis and consequences of the metabolic paradigm of a "truncated" Krebs/TCA cycle. Abundant data are presented for substrate utilization and membrane cholesterol enrichment in tumors that are consistent with criteria of the Warburg effect. From healthy cellular homeostasis to the uncontrolled proliferation of tumors, metabolic alterations center upon the loss of regulation of the cholesterol biosynthetic pathway. Deregulated tumor cholesterogenesis at the HMGR locus, generating enhanced carbon flux through the cholesterol synthesis pathway, is an absolute prerequisite for DNA synthesis and cell division. Therefore, expedited citrate efflux from cholesterol-enriched tumor mitochondria via the CTP/SLC25A1 citrate transporter is fundamental for sustaining the constant demand for cytosolic citrate that fuels the elevated flow of carbons from acetyl-CoA through the deregulated pathway of cholesterol biosynthesis.

Keywords:  Warburg effect; mitochondrial citrate export; truncated Krebs/TCA cycle; tumor cholesterogenesis; tumor membrane cholesterol

DOI:  https://doi.org/10.3389/fcell.2021.626316
ACS Omega. 2021 Mar 23. 6(11): 7815-7828

Power of an Organic Electron Acceptor in Modulation of Intracellular Mitochondrial Reactive Oxygen Species: Inducing JNK- and Caspase-Dependent Apoptosis of Cancer Cells.

Saswat Mohapatra, Gaurav Das, Varsha Gupta, Prasenjit Mondal, Masashi Nitani, Yutaka Ie, Shreyam Chatterjee, Yoshio Aso, Surajit Ghosh.

Here, we demonstrate an interesting strategy of modulating mitochondrial reactive oxygen species (ROS) using the organic electron acceptor molecule carbonyl-bridged bithiazole attached with bis-trifluoroacetophenone (BBT). This molecule was found to affect complex I activity. It has the propensity to bind close to the flavin mononucleotide site of complex I of mitochondria where it traps electron released from nicotinamide adenine dinucleotide (NADH) and elevates intracellular ROS, which suggests that the bridged carbonyl in BBT plays a crucial role in the acceptance of electron from NADH. We understand that the potential of the NADH/NAD+ redox couple and low-lying LUMO energy level of BBT are compatible with each other, thus favoring its entrapment of released electrons in complex I. This effect of BBT in ROS generation activates JNK and p38 stress-dependent pathways and resulted in mitochondrial-dependent apoptotic cell death with the reduction in expression of several important cyto-protecting factors (Hsp27 and NFκB), indicating its potential in inhibition of cancer cell relapse. Intriguingly, we found that BBT is not a P-glycoprotein substrate, which further reveals its excellent anticancer potential. This study enlightens us on how the power of electron acceptor ability became an emerging strategy for modulation of intracellular function.

DOI: https://doi.org/10.1021/acsomega.1c00308
Haematologica. 2021 Apr 01.

European Myeloma Network perspective on CAR T-Cell therapies for multiple myeloma.

Benedetto Bruno, Ralph Wäsch, Monika Engelhardt, Francesca Gay, Luisa Giaccone, Mattia D'Agostino, Luis-Gerardo Rodríguez-Lobato, Sophia Danhof, Nico Gagelmann, Nicolaus Kröger, Rakesh Popat, Niels W C J Van de Donk, Evangelos Terpos, Meletios A Dimopoulos, Pieter Sonneveld, Hermann Einsele, Mario Boccadoro.

Chimeric antigen receptor (CAR) T cells (CAR-T) have dramatically changed the treatment landscape of B-cell malignancies, providing a potential cure for relapsed/refractory patients. Long-term responses in patients with acute lymphoblastic leukemia and non Hodgkin lymphomas have encouraged further development in myeloma. In particular, B-cell maturation antigen (BCMA)-targeted CAR-T have established very promising results in heavily pre-treated patients. Moreover, CAR-T targeting other antigens (i.e., SLAMF7 and CD44v6) are currently under investigation. However, none of these current autologous therapies have been approved, and despite high overall response rates across studies, main issues such as long-term outcome, toxicities, treatment resistance, and management of complications limit as yet their widespread use. Here, we critically review the most important pre-clinical and clinical findings, recent advances in CAR-T against myeloma, as well as discoveries in the biology of a still incurable disease, that, all together, will further improve safety and efficacy in relapsed/refractory patients, urgently in need of novel treatment options.

DOI: https://doi.org/10.3324/haematol.2020.276402
Cells. 2021 Mar 04. pii: 543. [Epub ahead of print]10(3):

Cellular Immunotherapy Targeting Cancer Stem Cells: Preclinical Evidence and Clinical Perspective.

Chiara Donini, Ramona Rotolo, Alessia Proment, Massimo Aglietta, Dario Sangiolo, Valeria Leuci.

  The term "cancer stem cells" (CSCs) commonly refers to a subset of tumor cells endowed with stemness features, potentially involved in chemo-resistance and disease relapses. CSCs may present peculiar immunogenic features influencing their homeostasis within the tumor microenvironment. The susceptibility of CSCs to recognition and targeting by the immune system is a relevant issue and matter of investigation, especially considering the multiple emerging immunotherapy strategies. Adoptive cellular immunotherapies, especially those strategies encompassing the genetic redirection with chimeric antigen receptors (CAR), hold relevant promise in several tumor settings and might in theory provide opportunities for selective elimination of CSC subsets. Initial dedicated preclinical studies are supporting the potential targeting of CSCs by cellular immunotherapies, indirect evidence from clinical studies may be derived and new studies are ongoing. Here we review the main issues related to the putative immunogenicity of CSCs, focusing on and highlighting the existing evidence and opportunities for cellular immunotherapy approaches with T and non-T antitumor lymphocytes.

Keywords:  adoptive immunotherapy; cancer stem cells (CSCs); chimeric antigen receptor (CAR); immunotherapy

DOI:  https://doi.org/10.3390/cells10030543
Int J Mol Sci. 2021 Mar 24. pii: 3315. [Epub ahead of print]22(7):

Mitochondrial Fuel Dependence on Glutamine Drives Chemo-Resistance in the Cancer Stem Cells of Hepatocellular Carcinoma.

Alan Chun Kit Lee, Pui Man Lau, Yiu Wa Kwan, Siu Kai Kong.

  Chemo-resistance hinders treatment of patients with hepatocellular carcinoma. Although there are many models that can be found in the literature, the root mechanism to explain chemo-resistance is still not fully understood. To gain a better understanding of this phenomenon, a chemo-resistant line, R-HepG2, was developed from a chemo-sensitive HepG2 line through an exposure of doxorubicin (DOX). The R-HepG2 exhibited a cancer stem cell (CSC) phenotype with an over-expression of P-glycoprotein (P-gp), conferring it a significant enhancement in drug efflux and survival. With these observations, we hypothesize that metabolic alteration in this drug-resistant CSC is the root cause of chemo-resistance. Our results show that, unlike other metabolic-reprogrammed CSCs that exhibit glycolytic phenotype described by the "Warburg effect", the R-HepG2 was metabolically quiescent with glucose independence, high metabolic plasticity, and relied on glutamine metabolism via the mitochondria for its chemo-resistance Intriguingly, drug efflux by P-gp in R-HepG2 depended on the mitochondrial ATP fueled by glutamine instead of glycolytic ATP. Armed with these observations, we blocked the glutamine metabolism in the R-HepG2 and a significant reduction of DOX efflux was obtained. We exploited this metabolic vulnerability using a combination of DOX and metformin in a glutamine-free condition to target the R-HepG2, resulting in a significant DOX sensitization. In conclusion, our findings highlight the metabolic modulation of chemo-resistance in CSCs. We delineate the altered metabolism that drives chemo-resistance and offer a new approach to target this CSC through metabolic interventions.

Keywords:  P-glycoprotein; cancer cell metabolism; cancer stem cells; chemo-resistance; hepatocellular carcinoma; metabolic alteration; mitochondria

DOI:  https://doi.org/10.3390/ijms22073315
J Exp Clin Cancer Res. 2021 Mar 31. 40(1): 117

MITF induces escape from innate immunity in melanoma.

Luis Sánchez-Del-Campo, Román Martí-Díaz, María F Montenegro, Rebeca González-Guerrero, Trinidad Hernández-Caselles, Enrique Martínez-Barba, Antonio Piñero-Madrona, Juan Cabezas-Herrera, Colin R Goding, José Neptuno Rodríguez-López.

  BACKGROUND: The application of immune-based therapies has revolutionized cancer treatment. Yet how the immune system responds to phenotypically heterogeneous populations within tumors is poorly understood. In melanoma, one of the major determinants of phenotypic identity is the lineage survival oncogene MITF that integrates diverse microenvironmental cues to coordinate melanoma survival, senescence bypass, differentiation, proliferation, invasion, metabolism and DNA damage repair. Whether MITF also controls the immune response is unknown.METHODS: By using several mouse melanoma models, we examine the potential role of MITF to modulate the anti-melanoma immune response. ChIP-seq data analysis, ChIP-qPCR, CRISPR-Cas9 genome editing, and luciferase reporter assays were utilized to identify ADAM10 as a direct MITF target gene. Western blotting, confocal microscopy, flow cytometry, and natural killer (NK) cytotoxicity assays were used to determine the underlying mechanisms by which MITF-driven phenotypic plasticity modulates melanoma NK cell-mediated killing.
RESULTS: Here we show that MITF regulates expression of ADAM10, a key sheddase that cleaves the MICA/B family of ligands for NK cells. By controlling melanoma recognition by NK-cells MITF thereby controls the melanoma response to the innate immune system. Consequently, while melanoma MITFLow cells can be effectively suppressed by NK-mediated killing, MITF-expressing cells escape NK cell surveillance.
CONCLUSION: Our results reveal how modulation of MITF activity can impact the anti-melanoma immune response with implications for the application of anti-melanoma immunotherapies.

Keywords:  ADAM10; Anti-tumor immunity; MITF; Melanoma; NK-cells

DOI:  https://doi.org/10.1186/s13046-021-01916-8
Regen Ther. 2021 Jun;17 20-33

Immune evasion by cancer stem cells.

Hiroyuki Tsuchiya, Goshi Shiota.

  Tumor immunity represents a new avenue for cancer therapy. Immune checkpoint inhibitors have successfully improved outcomes in several tumor types. In addition, currently, immune cell-based therapy is also attracting significant attention. However, the clinical efficacy of these treatments requires further improvement. The mechanisms through which cancer cells escape the immune response must be identified and clarified. Cancer stem cells (CSCs) play a central role in multiple aspects of malignant tumors. CSCs can initiate tumors in partially immunocompromised mice, whereas non-CSCs fail to form tumors, suggesting that tumor initiation is a definitive function of CSCs. However, the fact that non-CSCs also initiate tumors in more highly immunocompromised mice suggests that the immune evasion property may be a more fundamental feature of CSCs rather than a tumor-initiating property. In this review, we summarize studies that have elucidated how CSCs evade tumor immunity and create an immunosuppressive milieu with a focus on CSC-specific characteristics and functions. These profound mechanisms provide important clues for the development of novel tumor immunotherapies.

Keywords:  ADCC, antibody-dependent cell mediated cytotoxicity; ALDH, alcohol dehydrogenase; AML, acute myeloid leukemia; ARID3B, AT-rich interaction domain-containing protein 3B; CCR7, C–C motif chemokine receptor 7; CIK, cytokine-induced killer cell; CMV, cytomegalovirus; CSC, cancer stem cell; CTL, cytotoxic T lymphocytes; CTLA-4, cytotoxic T-cell-associated antigen-4; Cancer stem cells; DC, dendritic cell; DNMT, DNA methyltransferase; EMT, epithelial–mesenchymal transition; ETO, fat mass and obesity associated protein; EV, extracellular vesicle; HNSCC, head and neck squamous cell carcinoma; Immune checkpoints; Immune evasion; KDM4, lysine-specific demethylase 4C; KIR, killer immunoglobulin-like receptor; LAG3, lymphocyte activation gene 3; LILR, leukocyte immunoglobulin-like receptor; LMP, low molecular weight protein; LOX, lysyl oxidase; MDSC, myeloid-derived suppressor cell; MHC, major histocompatibility complex; MIC, MHC class I polypeptide-related sequence; NGF, nerve growth factor; NK cells; NK, natural killer; NOD, nonobese diabetic; NSG, NOD/SCID IL-2 receptor gamma chain null; OCT4, octamer-binding transcription factor 4; PD-1, programmed death receptor-1; PD-L1/2, ligands 1/2; PI9, protease inhibitor 9; PSME3, proteasome activator subunit 3; SCID, severe combined immunodeficient; SOX2, sex determining region Y-box 2; T cells; TAM, tumor-associated macrophage; TAP, transporter associated with antigen processing; TCR, T cell receptor; Treg, regulatory T cell; ULBP, UL16 binding protein; uPAR, urokinase-type plasminogen activator receptor

DOI:  https://doi.org/10.1016/j.reth.2021.02.006
Cancers (Basel). 2021 Mar 24. pii: 1488. [Epub ahead of print]13(7):

The Importance of Mitochondrial Pyruvate Carrier in Cancer Cell Metabolism and Tumorigenesis.

Ainhoa Ruiz-Iglesias, Santos Mañes.

  Pyruvate is a key molecule in the metabolic fate of mammalian cells; it is the crossroads from where metabolism proceeds either oxidatively or ends with the production of lactic acid. Pyruvate metabolism is regulated by many enzymes that together control carbon flux. Mitochondrial pyruvate carrier (MPC) is responsible for importing pyruvate from the cytosol to the mitochondrial matrix, where it is oxidatively phosphorylated to produce adenosine triphosphate (ATP) and to generate intermediates used in multiple biosynthetic pathways. MPC activity has an important role in glucose homeostasis, and its alteration is associated with diabetes, heart failure, and neurodegeneration. In cancer, however, controversy surrounds MPC function. In some cancers, MPC upregulation appears to be associated with a poor prognosis. However, most transformed cells undergo a switch from oxidative to glycolytic metabolism, the so-called Warburg effect, which, amongst other possibilities, is induced by MPC malfunction or downregulation. Consequently, impaired MPC function might induce tumors with strong proliferative, migratory, and invasive capabilities. Moreover, glycolytic cancer cells secrete lactate, acidifying the microenvironment, which in turn induces angiogenesis, immunosuppression, and the expansion of stromal cell populations supporting tumor growth. This review examines the latest findings regarding the tumorigenic processes affected by MPC.

Keywords:  MPC; SLC; Warburg effect; glycolysis; lactate; mitochondrial matrix; oxidative phosphorylation

DOI:  https://doi.org/10.3390/cancers13071488
Nat Cancer. 2020 Nov;1(11): 1113-1127

Mutational and functional genetics mapping of chemotherapy resistance mechanisms in relapsed acute lymphoblastic leukemia.

Koichi Oshima, Junfei Zhao, Pablo Pérez-Durán, Jessie A Brown, Juan Angel Patiño-Galindo, Timothy Chu, Aidan Quinn, Thomas Gunning, Laura Belver, Alberto Ambesi-Impiombato, Valeria Tosello, Zhengqiang Wang, Maria Luisa Sulis, Motohiro Kato, Katsuyoshi Koh, Maddalena Paganin, Giuseppe Basso, Milagros Balbin, Concepcion Nicolas, Julie M Gastier-Foster, Meenakshi Devidas, Mignon L Loh, Elisabeth Paietta, Martin S Tallman, Jacob M Rowe, Mark Litzow, Mark D Minden, Jules Meijerink, Raul Rabadan, Adolfo Ferrando.

Multi-agent combination chemotherapy can be curative in acute lymphoblastic leukemia (ALL). Still, patients with primary refractory disease or with relapsed leukemia have a very poor prognosis. Here we integrate an in-depth dissection of the mutational landscape across diagnostic and relapsed pediatric and adult ALL samples with genome-wide CRISPR screen analysis of gene-drug interactions across seven ALL chemotherapy drugs. By combining these analyses, we uncover diagnostic and relapse-specific mutational mechanisms as well as genetic drivers of chemoresistance. Functionally, our data identifies common and drug-specific pathways modulating chemotherapy response and underscores the effect of drug combinations in restricting the selection of resistance-driving genetic lesions. In addition, by identifying actionable targets for the reversal of chemotherapy resistance, these analyses open novel therapeutic opportunities for the treatment of relapse and refractory disease.

DOI: https://doi.org/10.1038/s43018-020-00124-1
Front Oncol. 2021 ;11 617937

Overcoming Glucocorticoid Resistance in Acute Lymphoblastic Leukemia: Repurposed Drugs Can Improve the Protocol.

Miguel Olivas-Aguirre, Liliana Torres-López, Igor Pottosin, Oxana Dobrovinskaya.

  Glucocorticoids (GCs) are a central component of multi-drug treatment protocols against T and B acute lymphoblastic leukemia (ALL), which are used intensively during the remission induction to rapidly eliminate the leukemic blasts. The primary response to GCs predicts the overall response to treatment and clinical outcome. In this review, we have critically analyzed the available data on the effects of GCs on sensitive and resistant leukemic cells, in order to reveal the mechanisms of GC resistance and how these mechanisms may determine a poor outcome in ALL. Apart of the GC resistance, associated with a decreased expression of receptors to GCs, there are several additional mechanisms, triggered by alterations of different signaling pathways, which cause the metabolic reprogramming, with an enhanced level of glycolysis and oxidative phosphorylation, apoptosis resistance, and multidrug resistance. Due to all this, the GC-resistant ALL show a poor sensitivity to conventional chemotherapeutic protocols. We propose pharmacological strategies that can trigger alternative intracellular pathways to revert or overcome GC resistance. Specifically, we focused our search on drugs, which are already approved for treatment of other diseases and demonstrated anti-ALL effects in experimental pre-clinical models. Among them are some "truly" re-purposed drugs, which have different targets in ALL as compared to other diseases: cannabidiol, which targets mitochondria and causes the mitochondrial permeability transition-driven necrosis, tamoxifen, which induces autophagy and cell death, and reverts GC resistance through the mechanisms independent of nuclear estrogen receptors ("off-target effects"), antibiotic tigecycline, which inhibits mitochondrial respiration, causing energy crisis and cell death, and some anthelmintic drugs. Additionally, we have listed compounds that show a classical mechanism of action in ALL but are not used still in treatment protocols: the BH3 mimetic venetoclax, which inhibits the anti-apoptotic protein Bcl-2, the hypomethylating agent 5-azacytidine, which restores the expression of the pro-apoptotic BIM, and compounds targeting the PI3K-Akt-mTOR axis. Accordingly, these drugs may be considered for the inclusion into chemotherapeutic protocols for GC-resistant ALL treatments.

Keywords:  BH3 mimetics; acute lymphoblastic leukemia; cannabidiol; drug repositioning; glucocorticoid-resistance; signaling pathways; tamoxifen; tigecycline

DOI:  https://doi.org/10.3389/fonc.2021.617937
Int J Mol Sci. 2021 Mar 02. pii: 2490. [Epub ahead of print]22(5):

ANT1 Activation and Inhibition Patterns Support the Fatty Acid Cycling Mechanism for Proton Transport.

Jürgen Kreiter, Anne Rupprecht, Sanja Škulj, Zlatko Brkljača, Kristina Žuna, Denis G Knyazev, Sarah Bardakji, Mario Vazdar, Elena E Pohl.

  Adenine nucleotide translocase (ANT) is a well-known mitochondrial exchanger of ATP against ADP. In contrast, few studies have shown that ANT also mediates proton transport across the inner mitochondrial membrane. The results of these studies are controversial and lead to different hypotheses about molecular transport mechanisms. We hypothesized that the H+-transport mediated by ANT and uncoupling proteins (UCP) has a similar regulation pattern and can be explained by the fatty acid cycling concept. The reconstitution of purified recombinant ANT1 in the planar lipid bilayers allowed us to measure the membrane current after the direct application of transmembrane potential ΔΨ, which would correspond to the mitochondrial states III and IV. Experimental results reveal that ANT1 does not contribute to a basal proton leak. Instead, it mediates H+ transport only in the presence of long-chain fatty acids (FA), as already known for UCPs. It depends on FA chain length and saturation, implying that FA's transport is confined to the lipid-protein interface. Purine nucleotides with the preference for ATP and ADP inhibited H+ transport. Specific inhibitors of ATP/ADP transport, carboxyatractyloside or bongkrekic acid, also decreased proton transport. The H+ turnover number was calculated based on ANT1 concentration determined by fluorescence correlation spectroscopy and is equal to 14.6 ± 2.5 s-1. Molecular dynamic simulations revealed a large positively charged area at the protein/lipid interface that might facilitate FA anion's transport across the membrane. ANT's dual function-ADP/ATP and H+ transport in the presence of FA-may be important for the regulation of mitochondrial membrane potential and thus for potential-dependent processes in mitochondria. Moreover, the expansion of proton-transport modulating drug targets to ANT1 may improve the therapy of obesity, cancer, steatosis, cardiovascular and neurodegenerative diseases.

Keywords:  ADP/ATP carrier protein; arachidonic acid; fatty acid anion transport; long-chain fatty acids; mitochondrial transporter; proton transport

DOI:  https://doi.org/10.3390/ijms22052490
Cells. 2021 Mar 09. pii: 607. [Epub ahead of print]10(3):

The Role of Cytokines and Chemokines in Shaping the Immune Microenvironment of Glioblastoma: Implications for Immunotherapy.

Erica C F Yeo, Michael P Brown, Tessa Gargett, Lisa M Ebert.

  Glioblastoma is the most common form of primary brain tumour in adults. For more than a decade, conventional treatment has produced a relatively modest improvement in the overall survival of glioblastoma patients. The immunosuppressive mechanisms employed by neoplastic and non-neoplastic cells within the tumour can limit treatment efficacy, and this can include the secretion of immunosuppressive cytokines and chemokines. These factors can play a significant role in immune modulation, thus disabling anti-tumour responses and contributing to tumour progression. Here, we review the complex interplay between populations of immune and tumour cells together with defined contributions by key cytokines and chemokines to these intercellular interactions. Understanding how these tumour-derived factors facilitate the crosstalk between cells may identify molecular candidates for potential immunotherapeutic targeting, which may enable better tumour control and improved patient survival.

Keywords:  chemokine; cytokine; glioblastoma; immune suppression; microenvironment

DOI:  https://doi.org/10.3390/cells10030607
Front Oncol. 2021 ;11 632623

Reactive Oxygen Species Rewires Metabolic Activity in Acute Myeloid Leukemia.

Andrew J Robinson, Sara Davies, Richard L Darley, Alex Tonks.

  Acute myeloid leukemia (AML) is a heterogeneous disease with poor clinical outcomes. We have previously shown that constitutive activation of NADPH oxidase 2 (NOX2), resulting in over-production of reactive oxygen species (ROS), occurs in over 60% of AML patients. We have also shown that increased ROS production promotes increased glucose uptake and proliferation in AML cells, mediated by changes in carbohydrate metabolism. Given that carbohydrate, lipid, and protein metabolisms are all intricately interconnected, we aimed to examine the effect of cellular ROS levels on these pathways and establish further evidence that ROS rewires metabolism in AML. We carried out metabolomic profiling of AML cell lines in which NOX2-derived ROS production was inhibited and conversely in cells treated with exogenous H2O2. We report significant ROS-specific metabolic alterations in sphingolipid metabolism, fatty acid oxidation, purine metabolism, amino acid homeostasis and glycolysis. These data provide further evidence of ROS directed metabolic changes in AML and the potential for metabolic targeting as novel therapeutic arm to combat this disease.

Keywords:  NADPH Oxidase (NOX); acute myeloid leukemia; metabolism; reactive oxygen species; redox signaling

DOI:  https://doi.org/10.3389/fonc.2021.632623
Biomolecules. 2021 Mar 31. pii: 521. [Epub ahead of print]11(4):

The Mitochondrial Carnitine Acyl-carnitine Carrier (SLC25A20): Molecular Mechanisms of Transport, Role in Redox Sensing and Interaction with Drugs.

Annamaria Tonazzi, Nicola Giangregorio, Lara Console, Ferdinando Palmieri, Cesare Indiveri.

  The SLC25A20 transporter, also known as carnitine acyl-carnitine carrier (CAC), catalyzes the transport of short, medium and long carbon chain acyl-carnitines across the mitochondrial inner membrane in exchange for carnitine. The 30-year story of the protein responsible for this function started with its purification from rat liver mitochondria. Even though its 3D structure is not yet available, CAC is one of the most deeply characterized transport proteins of the inner mitochondrial membrane. Other than functional, kinetic and mechanistic data, post-translational modifications regulating the transport activity of CAC have been revealed. CAC interactions with drugs or xenobiotics relevant to human health and toxicology and the response of the carrier function to dietary compounds have been discovered. Exploiting combined approaches of site-directed mutagenesis with chemical targeting and bioinformatics, a large set of data on structure/function relationships have been obtained, giving novel information on the molecular mechanism of the transport catalyzed by this protein.

Keywords:  SLC25A20; carnitine; carnitine acyl-carnitine carrier; carnitine acyl-carnitine translocase; membrane transport; mitochondria; mitochondrial carrier; mitochondrial transporter; post-translational modification; solute carrier family 25

DOI:  https://doi.org/10.3390/biom11040521