scholarly journals Rewiring of Cancer Cell Metabolism by Mitochondrial VDAC1 Depletion Results in Time-Dependent Tumor Reprogramming: Glioblastoma as a Proof of Concept

Cells ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 1330 ◽  
Author(s):  
Arif ◽  
Stern ◽  
Pittala ◽  
Chalifa-Caspi ◽  
Shoshan-Barmatz
Keyword(s):  
Cancer Cell ◽  
Cell Metabolism ◽  
Anion Channel ◽  
Translocator Protein ◽  
Global Changes ◽  
Voltage Dependent Anion Channel ◽  
Oncogenic Signaling ◽  
Neuronal Markers ◽  
Long Period

Reprograming of the metabolism of cancer cells is an event recognized as a hallmark of the disease. The mitochondrial gatekeeper, voltage-dependent anion channel 1 (VDAC1), mediates transport of metabolites and ions in and out of mitochondria, and is involved in mitochondria-mediated apoptosis. Here, we compared the effects of reducing hVDAC1 expression in a glioblastoma xenograft using human-specific si-RNA (si-hVDAC1) for a short (19 days) and a long term (40 days). Tumors underwent reprograming, reflected in rewired metabolism, eradication of cancer stem cells (CSCs) and differentiation. Short- and long-term treatments of the tumors with si-hVDAC1 similarly reduced the expression of metabolism-related enzymes, and translocator protein (TSPO) and CSCs markers. In contrast, differentiation into cells expressing astrocyte or neuronal markers was noted only after a long period during which the tumor cells were hVDAC1-depleted. This suggests that tumor cell differentiation is a prolonged process that precedes metabolic reprograming and the “disappearance” of CSCs. Tumor proteomics analysis revealing global changes in the expression levels of proteins associated with signaling, synthesis and degradation of proteins, DNA structure and replication and epigenetic changes, all of which were highly altered after a long period of si-hVDAC1 tumor treatment. The depletion of hVDAC1 greatly reduced the levels of the multifunctional translocator protein TSPO, which is overexpressed in both the mitochondria and the nucleus of the tumor. The results thus show that VDAC1 depletion-mediated cancer cell metabolic reprograming involves a chain of events occurring in a sequential manner leading to a reversal of the unique properties of the tumor, indicative of the interplay between metabolism and oncogenic signaling networks.

scholarly journals Oncolytic Virotherapy: The Cancer Cell Side

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 939
Author(s):  
Marcelo Ehrlich ◽  
Eran Bacharach
Keyword(s):  
Viral Replication ◽  
Cancer Cell ◽  
Cell Metabolism ◽  
Tumor Development ◽  
Oncolytic Viruses ◽  
Oncogenic Signaling ◽  
Functional Connection ◽  
Immunity Genes ◽  
Cancer Cell Metabolism ◽  
Editing Process

Cell autonomous immunity genes mediate the multiple stages of anti-viral defenses, including recognition of invading pathogens, inhibition of viral replication, reprogramming of cellular metabolism, programmed-cell-death, paracrine induction of antiviral state, and activation of immunostimulatory inflammation. In tumor development and/or immunotherapy settings, selective pressure applied by the immune system results in tumor immunoediting, a reduction in the immunostimulatory potential of the cancer cell. This editing process comprises the reduced expression and/or function of cell autonomous immunity genes, allowing for immune-evasion of the tumor while concomitantly attenuating anti-viral defenses. Combined with the oncogene-enhanced anabolic nature of cancer-cell metabolism, this attenuation of antiviral defenses contributes to viral replication and to the selectivity of oncolytic viruses (OVs) towards malignant cells. Here, we review the manners by which oncogene-mediated transformation and tumor immunoediting combine to alter the intracellular milieu of tumor cells, for the benefit of OV replication. We also explore the functional connection between oncogenic signaling and epigenetic silencing, and the way by which restriction of such silencing results in immune activation. Together, the picture that emerges is one in which OVs and epigenetic modifiers are part of a growing therapeutic toolbox that employs activation of anti-tumor immunity for cancer therapy.

scholarly journals TSPO: kaleidoscopic 18-kDa amid biochemical pharmacology, control and targeting of mitochondria

2016 ◽  
Vol 473 (2) ◽  
pp. 107-121 ◽  
Author(s):  
Jemma Gatliff ◽  
Michelangelo Campanella
Keyword(s):  
Neurological Diseases ◽  
Anion Channel ◽  
Translocator Protein ◽  
Endocrine Regulation ◽  
Voltage Dependent Anion Channel ◽  
Steroid Synthesis ◽  
Cellular Processes ◽  
Cellular Events ◽  
Voltage Dependent

The 18-kDa translocator protein (TSPO) localizes in the outer mitochondrial membrane (OMM) of cells and is readily up-regulated under various pathological conditions such as cancer, inflammation, mechanical lesions and neurological diseases. Able to bind with high affinity synthetic and endogenous ligands, its core biochemical function resides in the translocation of cholesterol into the mitochondria influencing the subsequent steps of (neuro-)steroid synthesis and systemic endocrine regulation. Over the years, however, TSPO has also been linked to core cellular processes such as apoptosis and autophagy. It interacts and forms complexes with other mitochondrial proteins such as the voltage-dependent anion channel (VDAC) via which signalling and regulatory transduction of these core cellular events may be influenced. Despite nearly 40 years of study, the precise functional role of TSPO beyond cholesterol trafficking remains elusive even though the recent breakthroughs on its high-resolution crystal structure and contribution to quality-control signalling of mitochondria. All this along with a captivating pharmacological profile provides novel opportunities to investigate and understand the significance of this highly conserved protein as well as contribute the development of specific therapeutics as presented and discussed in the present review.

scholarly journals VDAC1 at the Intersection of Cell Metabolism, Apoptosis, and Diseases

Biomolecules ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 1485 ◽  
Author(s):  
Varda Shoshan-Barmatz ◽  
Anna Shteinfer-Kuzmine ◽  
Ankit Verma
Keyword(s):  
Cell Metabolism ◽  
Anion Channel ◽  
Outer Mitochondrial Membrane ◽  
Voltage Dependent Anion Channel ◽  
Pathological Conditions ◽  
Large Channel ◽  
Voltage Dependent ◽  
Important Regulator ◽  
Apoptotic Proteins ◽  
Interferon Responses

The voltage-dependent anion channel 1 (VDAC1) protein, is an important regulator of mitochondrial function, and serves as a mitochondrial gatekeeper, with responsibility for cellular fate. In addition to control over energy sources and metabolism, the protein also regulates epigenomic elements and apoptosis via mediating the release of apoptotic proteins from the mitochondria. Apoptotic and pathological conditions, as well as certain viruses, induce cell death by inducing VDAC1 overexpression leading to oligomerization, and the formation of a large channel within the VDAC1 homo-oligomer. This then permits the release of pro-apoptotic proteins from the mitochondria and subsequent apoptosis. Mitochondrial DNA can also be released through this channel, which triggers type-Ι interferon responses. VDAC1 also participates in endoplasmic reticulum (ER)-mitochondria cross-talk, and in the regulation of autophagy, and inflammation. Its location in the outer mitochondrial membrane, makes VDAC1 ideally placed to interact with over 100 proteins, and to orchestrate the interaction of mitochondrial and cellular activities through a number of signaling pathways. Here, we provide insights into the multiple functions of VDAC1 and describe its involvement in several diseases, which demonstrate the potential of this protein as a druggable target in a wide variety of pathologies, including cancer.

scholarly journals A Novel Interaction of Translocator Protein 18 kDa (TSPO) with NADPH Oxidase in Microglia

2020 ◽  
Vol 57 (11) ◽  
pp. 4467-4487
Author(s):  
Meredith K. Loth ◽  
Sara R. Guariglia ◽  
Diane B. Re ◽  
Juan Perez ◽  
Vanessa Nunes de Paiva ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Redox Homeostasis ◽  
Anion Channel ◽  
Translocator Protein ◽  
Lower Amount ◽  
Proximity Ligation Assay ◽  
Ros Production ◽  
Voltage Dependent Anion Channel ◽  
Murine Microglia ◽  
Translocator Protein 18 Kda

Abstract In the brain neuropil, translocator protein 18 kDa (TSPO) is a stress response protein that is upregulated in microglia and astrocytes in diverse central nervous system pathologies. TSPO is widely used as a biomarker of neuroinflammation in preclinical and clinical neuroimaging studies. However, there is a paucity of knowledge on the function(s) of TSPO in glial cells. In this study, we explored a putative interaction between TSPO and NADPH oxidase 2 (NOX2) in microglia. We found that TSPO associates with gp91phox and p22phox, the principal subunits of NOX2 in primary murine microglia. The association of TSPO with gp91phox and p22phox was observed using co-immunoprecipitation, confocal immunofluorescence imaging, and proximity ligation assay. We found that besides gp91phox and p22phox, voltage-dependent anion channel (VDAC) also co-immunoprecipitated with TSPO consistent with previous reports. When we compared lipopolysaccharide (LPS) stimulated microglia to vehicle control, we found that a lower amount of gp91phox and p22phox protein co-immunoprecipitated with TSPO suggesting a disruption of the TSPO-NOX2 subunits association. TSPO immuno-gold electron microscopy confirmed that TSPO is present in the outer mitochondrial membrane but it is also found in the endoplasmic reticulum (ER), mitochondria-associated ER membrane (MAM), and in the plasma membrane. TSPO localization at the MAM may represent a subcellular site where TSPO interacts with gp91phox and p22phox since the MAM is a point of communication between outer mitochondria membrane proteins (TSPO) and ER proteins (gp91phox and p22phox) where they mature and form the cytochrome b558 (Cytb558) heterodimer. We also found that an acute burst of reactive oxygen species (ROS) increased TSPO levels on the surface of microglia and this effect was abrogated by a ROS scavenger. These results suggest that ROS production may alter the subcellular distribution of TSPO. Collectively, our findings suggest that in microglia, TSPO is associated with the major NOX2 subunits gp91phox and p22phox. We hypothesize that this interaction may regulate Cytb558 formation and modulate NOX2 levels, ROS production, and redox homeostasis in microglia.

TSPO is a REDOX regulator of cell mitophagy

2015 ◽  
Vol 43 (4) ◽  
pp. 543-552 ◽  
Author(s):  
Jemma Gatliff ◽  
Michelangelo Campanella
Keyword(s):  
Cell Biology ◽  
Anion Channel ◽  
Translocator Protein ◽  
Control Mechanisms ◽  
Voltage Dependent Anion Channel ◽  
Core Element ◽  
Functional Link ◽  
Positron Emission

The mitochondrial 18-kDa translocator protein (TSPO) was originally discovered as a peripheral binding site of benzodiazepines to be later described as a core element of cholesterol trafficking between cytosol and mitochondria from which the current nomenclature originated. The high affinity it exhibits with chemicals (i.e. PK11195) has generated interest in the development of mitochondrial based TSPO-binding drugs for in vitro and in vivo analysis. Increased TSPO expression is observed in numerous pathologies such as cancer and inflammatory conditions of the central nervous system (CNS) that have been successfully exploited via protocols of positron emission tomography (PET) imaging. We endeavoured to dissect the molecular role of TSPO in mitochondrial cell biology and discovered a functional link with quality control mechanisms operated by selective autophagy. This review focuses on the current understanding of this pathway and focuses on the interplay with reactive oxygen species (ROS) and the voltage-dependent anion channel (VDAC), to which TSPO binds, in the regulation of cell mitophagy and hence homoeostasis of the mitochondrial network as a whole.

In vitro Effects of the Specific Mitochondrial TSPO Ligand Ro5 4864 in Cultured Human Osteoblasts

2017 ◽  
Vol 126 (02) ◽  
pp. 77-84 ◽  
Author(s):  
Nahum Rosenberg ◽  
Orit Rosenberg ◽  
Abraham Weizman ◽  
Leo Veenman ◽  
Moshe Gavish
Keyword(s):  
Protein Expression ◽  
Cellular Proliferation ◽  
Protoporphyrin Ix ◽  
Anion Channel ◽  
Translocator Protein ◽  
Mitochondrial Activity ◽  
Voltage Dependent Anion Channel ◽  
Hexokinase 2 ◽  
Human Osteoblasts

AbstractThe 18 kDa mitochondrial translocator protein (TSPO) ligands (10 µM), e. g., protoporphyrin IX, PK 11195 and FGIN-1-27, have different effects on metabolism and protein expression in human osteoblasts. In this study, we investigated the archetypical TSPO specific ligand Ro5-4864 (10 µM) effect in primary osteoblasts in culture aiming to further understand the TSPO role in these mature metabolically active cells.We found that following exposure to Ro5-4864, cellular [18F]-FDG incorporation and ATP content were reduced by 48% (p<0.001) and 44% (p<0.001), respectively. The mitochondrial membrane potential (ΔΨm) increased by 50% (p<0.01), mRNA synthesis of TSPO and voltage dependent anion channel (VDAC1) decreased both by 70%, the TSPO and VDAC1 protein expression decreased by 80% and 68%, respectively (p<0.001). Ro5 4864 caused a decrease in the proportion of cells in the G1 phase (by 20%, p<0.05), shifting the cell cycle to the S and G2/M phases. Furthermore, 63% decrease in hexokinase 2 protein expression (p<0.001) was found. However, we found no significant effects on hexokinase 2 mRNA expression (by RT-PCR). We also did not see significant changes in mitochondrial mass (MitoTracker Green assay), apoptosis rate (TUNEL assay), overall cell death (LDH assay), cellular proliferation (BrdU assay), cell maturation (cellular alkaline phosphatase assay), and the number of cells in the culture.Therefore, an overall effect of Ro5-4864 exhorts is via pathways related to the mitochondrial activity, which is only partly like PK 11195, but not to the other TSPO ligands.

scholarly journals WNT Signaling: an Emerging Mediator of Cancer Cell Metabolism?

2014 ◽  
Vol 35 (1) ◽  
pp. 2-10 ◽  
Author(s):  
Victoria Sherwood
Keyword(s):  
Wnt Signaling ◽  
Signaling Pathways ◽  
Cancer Cell ◽  
Cancer Metabolism ◽  
Cell Metabolism ◽  
Critical Role ◽  
Oncogenic Signaling ◽  
Cancer Cell Metabolism ◽  
Oncogenic Signaling Pathways

WNT signaling was discovered in tumor models and has been recognized as a regulator of cancer development and progression for over 3 decades. Recent work has highlighted a critical role for WNT signaling in the metabolic homeostasis of mammals, where its misregulation has been heavily implicated in diabetes. While the majority of WNT metabolism research has focused on nontransformed tissues, the role of WNT in cancer metabolism remains underinvestigated. Cancer is also a metabolic disease where oncogenic signaling pathways regulate energy production and macromolecular synthesis to fuel rapidly proliferating tumors. This review highlights the emerging evidence for WNT signaling in the reprogramming of cancer cell metabolism and examines the role of these signaling pathways as mediators of tumor bioenergetics.

scholarly journals Evidences of a Direct Relationship between Cellular Fuel Supply and Ciliogenesis Regulated by Hypoxic VDAC1-ΔC

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3484
Author(s):  
Monique Meyenberg Cunha-de Padua ◽  
Lucilla Fabbri ◽  
Maeva Dufies ◽  
Sandra Lacas-Gervais ◽  
Julie Contenti ◽  
...  
Keyword(s):  
Direct Relationship ◽  
Cell Metabolism ◽  
Genetic Disorders ◽  
Phosphorylation Site ◽  
Anion Channel ◽  
Metabolic Flexibility ◽  
Apoptosis Resistance ◽  
Voltage Dependent Anion Channel ◽  
Putative Phosphorylation Site ◽  
Voltage Dependent

Metabolic flexibility is the ability of a cell to adapt its metabolism to changes in its surrounding environment. Such adaptability, combined with apoptosis resistance provides cancer cells with a survival advantage. Mitochondrial voltage-dependent anion channel 1 (VDAC1) has been defined as a metabolic checkpoint at the crossroad of these two processes. Here, we show that the hypoxia-induced cleaved form of VDAC1 (VDAC1-ΔC) is implicated in both the up-regulation of glycolysis and the mitochondrial respiration. We demonstrate that VDAC1-ΔC, due to the loss of the putative phosphorylation site at serine 215, concomitantly with the loss of interaction with tubulin and microtubules, reprograms the cell to utilize more metabolites, favoring cell growth in hypoxic microenvironment. We further found that VDAC1-ΔC represses ciliogenesis and thus participates in ciliopathy, a group of genetic disorders involving dysfunctional primary cilium. Cancer, although not representing a ciliopathy, is tightly linked to cilia. Moreover, we highlight, for the first time, a direct relationship between the cilium and cancer cell metabolism. Our study provides the first new comprehensive molecular-level model centered on VDAC1-ΔC integrating metabolic flexibility, ciliogenesis, and enhanced survival in a hypoxic microenvironment.

Sign in / Sign up

Export Citation Format

Share Document