scholarly journals The down-regulation of miR-125b in chronic lymphocytic leukemias leads to metabolic adaptation of cells to a transformed state

Blood ◽  
2012 ◽  
Vol 120 (13) ◽  
pp. 2631-2638 ◽  
Author(s):  
Esmerina Tili ◽  
Jean-Jacques Michaille ◽  
Zhenghua Luo ◽  
Stefano Volinia ◽  
Laura Z. Rassenti ◽  
...  
Keyword(s):  
Cell Lines ◽  
Metabolic Pathways ◽  
Chromosomal Region ◽  
Cell Metabolism ◽  
Metabolic Adaptation ◽  
Therapeutic Approaches ◽  
Down Regulation ◽  
Master Regulator ◽  
Transcript Signature ◽  
Novel Therapeutic

Abstract MiR-125b-1 maps at 11q24, a chromosomal region close to the epicenter of 11q23 deletions in chronic lymphocytic leukemias (CLLs). Our results establish that both aggressive and indolent CLL patients show reduced expression of miR-125b. Overexpression of miR-125b in CLL-derived cell lines resulted in the repression of many transcripts encoding enzymes implicated in cell metabolism. Metabolomics analyses showed that miR-125b overexpression modulated glucose, glutathione, lipid, and glycerolipid metabolism. Changes on the same metabolic pathways also were observed in CLLs. We furthermore analyzed the expression of some of miR-125b–target transcripts that are potentially involved in the aforementioned metabolic pathways and defined a miR-125b–dependent CLL metabolism-related transcript signature. Thus, miR-125b acts as a master regulator for the adaptation of cell metabolism to a transformed state. MiR-125b and miR-125b–dependent metabolites therefore warrant further investigation as possible novel therapeutic approaches for patients with CLL.

scholarly journals Targeted enzyme assisted chemotherapy (TEAC) – a novel microRNA-guided and selenium-based regimen to specifically eradicate hepatocellular carcinoma

2021 ◽  
Author(s):  
Arun Kumar Selvam ◽  
Rim Jawad ◽  
Roberto Gramignoli ◽  
Adnane Achour ◽  
Hugh Salter ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Lines ◽  
Human Hepatocytes ◽  
Hepatic Tumors ◽  
Therapeutic Approaches ◽  
Specific Induction ◽  
Specific Cytotoxicity ◽  
Hcc Cells ◽  
Novel Therapeutic ◽  
Target Effects

AbstractDespite progress in the treatment of non-visceral malignancies, the prognosis remains poor for malignancies of visceral organs and novel therapeutic approaches are urgently required. Here we introduce a novel therapeutic regimen by treatment with Se-methylselenocysteine (MSC) and concomitant tumor-specific induction of Kynurenine aminotransferase 1 (KYAT1) in hepatocellular carcinoma (HCC) cell lines, using either vector-based and/or lipid nanoparticle-mediated delivery of mRNA. Supplementation of MSC in KYAT1 overexpressed cells resulted in significantly increased cytotoxicity as compared to MSC alone. Furthermore, microRNA antisense targeted sites for miR122, known to be widely expressed in normal hepatocytes whilst downregulated in hepatocellular carcinoma, were added to specifically limit cytotoxicity in HCC cells, thereby limiting off-target effects. KYAT1 expression was significantly reduced in cells with high levels of miR122 supporting the concept of miR-guided induction of tumor-specific cytotoxicity. The addition of alpha-ketoacid favored the production of methylselenol, enhancing the cytotoxic efficacy of MSC in HCC cells, with no effects on primary human hepatocytes. Altogether, the proposed regimen offers great potential to safely and specifically target hepatic tumors that are currently untreatable.

scholarly journals Emergence of MicroRNAs as Key Players in Cancer Cell Metabolism

2019 ◽  
Vol 65 (9) ◽  
pp. 1090-1101 ◽  
Author(s):  
Sugarniya Subramaniam ◽  
Varinder Jeet ◽  
Judith A Clements ◽  
Jennifer H Gunter ◽  
Jyotsna Batra
Keyword(s):  
Fatty Acid ◽  
Signaling Pathways ◽  
Tumor Cells ◽  
Metabolic Pathways ◽  
Acid Metabolism ◽  
Tca Cycle ◽  
Metabolic Reprogramming ◽  
Metabolic Adaptation ◽  
Novel Therapeutic

AbstractBACKGROUNDMetabolic reprogramming is a hallmark of cancer. MicroRNAs (miRNAs) have been found to regulate cancer metabolism by regulating genes involved in metabolic pathways. Understanding this layer of complexity could lead to the development of novel therapeutic approaches.CONTENTmiRNAs are noncoding RNAs that have been implicated as master regulators of gene expression. Studies have revealed the role of miRNAs in the metabolic reprogramming of tumor cells, with several miRNAs both positively and negatively regulating multiple metabolic genes. The tricarboxylic acid (TCA) cycle, aerobic glycolysis, de novo fatty acid synthesis, and altered autophagy allow tumor cells to survive under adverse conditions. In addition, major signaling molecules, hypoxia-inducible factor, phosphatidylinositol-3 kinase/protein kinase B/mammalian target of rapamycin/phosphatase and tensin homolog, and insulin signaling pathways facilitate metabolic adaptation in tumor cells and are all regulated by miRNAs. Accumulating evidence suggests that miRNA mimics or inhibitors could be used to modulate the activity of miRNAs that drive tumor progression via altering their metabolism. Currently, several clinical trials investigating the role of miRNA-based therapy for cancer have been launched that may lead to novel therapeutic interventions in the future.SUMMARYIn this review, we summarize cancer-related metabolic pathways, including glycolysis, TCA cycle, pentose phosphate pathway, fatty acid metabolism, amino acid metabolism, and other metabolism-related oncogenic signaling pathways, and their regulation by miRNAs that are known to lead to tumorigenesis. Further, we discuss the current state of miRNA therapeutics in the clinic and their future potential.

scholarly journals Hypercapnia-inducible factor: a hypothesis

2021 ◽  
Vol 2 (3 2021) ◽  
pp. 27-31
Author(s):  
Khachik Muradian ◽  
Vadim Fraifeld
Keyword(s):  
Gene Expression ◽  
Key Words ◽  
Metabolic Pathways ◽  
Down Regulation ◽  
Master Regulator ◽  
Master Genes ◽  
Sense And Respond ◽  
First Time

Abstract. Cells and tissues sense and respond to hypercapnia by global activation or down-regulation of hundreds of genes and switching on/off a number of signaling and metabolic pathways. We hypothesize for the first time that such complex rearrangements are hardly possible without subtle guidance by a specific master regulator which we suggest to name hypercapnia-inducible factor (HcIF). Whether there are structural and functional similarities between HcIF and HIF remain to be elucidated. However, there are reasons to believe that, as master genes, HcIF and HIF can cooperate or compete depending on the situation. Only further research will warrant existence of HcIF as a molecular master regulator of the response to hypercapnia. Key words: hypercapnia, hypoxia, gene expression, aging

scholarly journals CBMT-39. TARGETING METABOLIC PATHWAYS IN HYPOXIA FOR GLIOBLASTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi41-vi41
Author(s):  
Aleksandra Gruslova ◽  
Alessia Lodi ◽  
Mengxing Li ◽  
Mei Zhou ◽  
Michael Garcia ◽  
...  
Keyword(s):  
Gene Expression ◽  
Overall Survival ◽  
Cell Line ◽  
Cell Lines ◽  
Metabolic Pathways ◽  
Progression Free Survival ◽  
Metabolic Adaptation ◽  
Metabolic Resistance ◽  
Free Survival ◽  
Hypoxic Volume

Abstract BACKGROUND Metabolic adaptation to hypoxia is a crucial consideration in combating anti-angiogenic resistance. We previously explored the potential of targeting the peroxisomal fatty acid oxidation (FAO) pathway and observed higher potency to peroxisomal FAO inhibitor thioridazine in hypoxia in vitro. In this study we further examine the effects of peroxisomal FAO enzyme ACOX1, looking at differences in mitochondrial and peroxisomal FAO in hypoxia between subtypes, and explore additional metabolic pathways that can be potentially further studied. METHODS We utilized a CRISPR doxycycline-inducible U251 knockout cell line for the peroxisomal FAO gene ACOX1 and examined growth and viability in 2 weeks hypoxia (2% O2). We analyzed the gene expression of 13 peroxisomal and mitochondrial FAO enzymes in six different patient-derived cell lines. Finally, we characterized serum metabolites that are associated with tumor hypoxic volume, progression-free survival, and overall survival in patients undergoing clinical trial for TH302 and bevacizumab with bevacizumab refractory tumors. RESULTS We observed decreased cell growth and viability (p < .03) specifically in hypoxia but not normoxia with ACOX1 knock out. We saw some changes in gene expression (|ΔΔCt| >1) in hypoxia for all genes, which differed between cell lines. ACOX1 and CPT1A expression were strongly decreased (|ΔΔCt| >2) while ACADSB expression was strongly increased for the proneural cell line. ACOX1 expression was strongly decreased in our most thioridazine-sensitive cell line. ACOX2, ACADVL, CPT1A, CPT1C, and DECR2 expression were strongly increased in one of the proneural cell lines. Twelve polar metabolites were positively or negatively correlated (|r| >.4) with both hypoxic volume and either overall survival or progression-free survival. CONCLUSION Peroxisomal FAO and other metabolic pathways may be essential to target in order combat metabolic resistance during anti-angiogenic therapy. Better understanding differences in metabolism in different tumor environments will help determine which targets will be most therapeutically useful.

scholarly journals Targeting the NAD Salvage Synthesis Pathway as a Novel Therapeutic Strategy for Osteosarcomas with Low NAPRT Expression

2021 ◽  
Vol 22 (12) ◽  
pp. 6273
Author(s):  
Natasja Franceschini ◽  
Jan Oosting ◽  
Maud Tamsma ◽  
Bertine Niessen ◽  
Inge Briaire-de Bruijn ◽  
...  
Keyword(s):  
Cell Lines ◽  
Metabolic Pathways ◽  
Therapeutic Strategy ◽  
Rna Expression ◽  
Primary Tumors ◽  
Nicotinamide Phosphoribosyltransferase ◽  
Nad Synthesis ◽  
Vitro Model ◽  
Novel Therapeutic

For osteosarcoma (OS), the most common primary malignant bone tumor, overall survival has hardly improved over the last four decades. Especially for metastatic OS, novel therapeutic targets are urgently needed. A hallmark of cancer is aberrant metabolism, which justifies targeting metabolic pathways as a promising therapeutic strategy. One of these metabolic pathways, the NAD+ synthesis pathway, can be considered as a potential target for OS treatment. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the classical salvage pathway for NAD+ synthesis, and NAMPT is overexpressed in OS. In this study, five OS cell lines were treated with the NAMPT inhibitor FK866, which was shown to decrease nuclei count in a 2D in vitro model without inducing caspase-driven apoptosis. The reduction in cell viability by FK866 was confirmed in a 3D model of OS cell lines (n = 3). Interestingly, only OS cells with low nicotinic acid phosphoribosyltransferase domain containing 1 (NAPRT1) RNA expression were sensitive to NAMPT inhibition. Using a publicly available (Therapeutically Applicable Research to Generate Effective Treatments (TARGET)) and a previously published dataset, it was shown that in OS cell lines and primary tumors, low NAPRT1 RNA expression correlated with NAPRT1 methylation around the transcription start site. These results suggest that targeting NAMPT in osteosarcoma could be considered as a novel therapeutic strategy, where low NAPRT expression can serve as a biomarker for the selection of eligible patients.

scholarly journals Is nuclear sirtuin SIRT6 a master regulator of immune function?

2020 ◽  
Author(s):  
Vinodkumar B Pillai ◽  
Mahesh P Gupta
Keyword(s):  
Immune Cells ◽  
Metabolic Pathways ◽  
Warburg Effect ◽  
Immune Cell ◽  
Cell Metabolism ◽  
Negative Regulator ◽  
Master Regulator ◽  
Energy Needs ◽  
And Function ◽  
The Warburg Effect

Abstract: The ability to ward off pathogens with minimal damage to the host determines the immune system's robustness. Multiple factors, including pathogen processing, identification, secretion of mediator and effector molecules, and immune cell proliferation and differentiation into various subsets, constitute the success of mounting an effective immune response. Cellular metabolism controls all of these intricate processes. Cells utilize diverse fuel sources and switch back and forth between different metabolic pathways depending on their energy needs. The three most critical metabolic pathways on which immune cells depend to meet their energy needs are oxidative metabolism, glycolysis, and glutaminolysis. Dynamic switching between these metabolic pathways is needed for optimal function of the immune cells. Moreover, switching between these metabolic pathways needs to be tightly regulated to achieve the best results. Immune cells depend on the Warburg effect for their growth, proliferation, secretory, and effector functions. Here, we hypothesize that the sirtuin, SIRT6, could be a negative regulator of the Warburg effect. We also postulate that SIRT6 could act as a master regulator of immune cell metabolism and function by regulating critical signaling pathways.

scholarly journals A Novel mRNA-Mediated and MicroRNA-Guided Approach to Specifically Eradicate Drug-Resistant Hepatocellular Carcinoma Cell Lines by Se-Methylselenocysteine

Antioxidants ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1094
Author(s):  
Arun Kumar Selvam ◽  
Rim Jawad ◽  
Roberto Gramignoli ◽  
Adnane Achour ◽  
Hugh Salter ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Lines ◽  
Therapeutic Approaches ◽  
Carcinoma Cell Lines ◽  
Specific Induction ◽  
Specific Cytotoxicity ◽  
Ros Formation ◽  
Hcc Cells ◽  
Novel Therapeutic ◽  
Target Effects

Despite progress in the treatment of non-visceral malignancies, the prognosis remains poor for malignancies of visceral organs and novel therapeutic approaches are urgently required. We evaluated a novel therapeutic regimen based on treatment with Se-methylselenocysteine (MSC) and concomitant tumor-specific induction of Kynurenine aminotransferase 1 (KYAT1) in hepatocellular carcinoma (HCC) cell lines, using either vector-based and/or lipid nanoparticle-mediated delivery of mRNA. Supplementation of MSC in KYAT1 overexpressed cells resulted in significantly increased cytotoxicity, due to ROS formation, as compared to MSC alone. Furthermore, microRNA antisense-targeted sites for miR122, known to be widely expressed in normal hepatocytes while downregulated in hepatocellular carcinoma, were added to specifically limit cytotoxicity in HCC cells, thereby limiting the off-target effects. KYAT1 expression was significantly reduced in cells with high levels of miR122 supporting the concept of miR-guided induction of tumor-specific cytotoxicity. The addition of alpha-ketoacid favored the production of methylselenol, enhancing the cytotoxic efficacy of MSC in HCC cells, with no effects on primary human hepatocytes. Altogether, the proposed regimen offers great potential to safely and specifically target hepatic tumors that are currently untreatable.

Adipocytes-released Peptides Involved in the Control of Gastrointestinal Motility

2019 ◽  
Vol 20 (6) ◽  
pp. 614-629 ◽  
Author(s):  
Eglantina Idrizaj ◽  
Rachele Garella ◽  
Roberta Squecco ◽  
Maria Caterina Baccari
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Adipose Tissue ◽  
Gastrointestinal Motility ◽  
Diagnostic Tools ◽  
Therapeutic Approaches ◽  
Motor Responses ◽  
Gastrointestinal Motor ◽  
Treatment Of Obesity ◽  
Novel Therapeutic

The present review focuses on adipocytes-released peptides known to be involved in the control of gastrointestinal motility, acting both centrally and peripherally. Thus, four peptides have been taken into account: leptin, adiponectin, nesfatin-1, and apelin. The discussion of the related physiological or pathophysiological roles, based on the most recent findings, is intended to underlie the close interactions among adipose tissue, central nervous system, and gastrointestinal tract. The better understanding of this complex network, as gastrointestinal motor responses represent peripheral signals involved in the regulation of food intake through the gut-brain axis, may also furnish a cue for the development of either novel therapeutic approaches in the treatment of obesity and eating disorders or potential diagnostic tools.

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