scholarly journals Targeting the Mitochondrial Metabolic Network: A Promising Strategy in Cancer Treatment

2020 ◽  
Vol 21 (17) ◽  
pp. 6014 ◽  
Author(s):  
Luca Frattaruolo ◽  
Matteo Brindisi ◽  
Rosita Curcio ◽  
Federica Marra ◽  
Vincenza Dolce ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Metabolic Network ◽  
Mitochondrial Dynamics ◽  
Tricarboxylic Acid Cycle ◽  
Critical Role ◽  
Metabolic Reprogramming ◽  
High Proliferation Rate ◽  
Preclinical And Clinical Studies ◽  
The Warburg Effect

Metabolic reprogramming is a hallmark of cancer, which implements a profound metabolic rewiring in order to support a high proliferation rate and to ensure cell survival in its complex microenvironment. Although initial studies considered glycolysis as a crucial metabolic pathway in tumor metabolism reprogramming (i.e., the Warburg effect), recently, the critical role of mitochondria in oncogenesis, tumor progression, and neoplastic dissemination has emerged. In this report, we examined the main mitochondrial metabolic pathways that are altered in cancer, which play key roles in the different stages of tumor progression. Furthermore, we reviewed the function of important molecules inhibiting the main mitochondrial metabolic processes, which have been proven to be promising anticancer candidates in recent years. In particular, inhibitors of oxidative phosphorylation (OXPHOS), heme flux, the tricarboxylic acid cycle (TCA), glutaminolysis, mitochondrial dynamics, and biogenesis are discussed. The examined mitochondrial metabolic network inhibitors have produced interesting results in both preclinical and clinical studies, advancing cancer research and emphasizing that mitochondrial targeting may represent an effective anticancer strategy.

scholarly journals Metabolic reprogramming via PPARα signaling in cardiac hypertrophy and failure: From metabolomics to epigenetics

2017 ◽  
Vol 313 (3) ◽  
pp. H584-H596 ◽  
Author(s):  
Junco Shibayama Warren ◽  
Shin-ichi Oka ◽  
Daniela Zablocki ◽  
Junichi Sadoshima
Keyword(s):  
Cardiac Hypertrophy ◽  
Current Knowledge ◽  
Critical Role ◽  
Cardiac Metabolism ◽  
Metabolic Reprogramming ◽  
Metabolic Phenotype ◽  
Global Changes ◽  
Peroxisome Proliferator ◽  
Metabolic Remodeling

Studies using omics-based approaches have advanced our knowledge of metabolic remodeling in cardiac hypertrophy and failure. Metabolomic analysis of the failing heart has revealed global changes in mitochondrial substrate metabolism. Peroxisome proliferator-activated receptor-α (PPARα) plays a critical role in synergistic regulation of cardiac metabolism through transcriptional control. Metabolic reprogramming via PPARα signaling in heart failure ultimately propagates into myocardial energetics. However, emerging evidence suggests that the expression level of PPARα per se does not always explain the energetic state in the heart. The transcriptional activities of PPARα are dynamic, yet highly coordinated. An additional level of complexity in the PPARα regulatory mechanism arises from its ability to interact with various partners, which ultimately determines the metabolic phenotype of the diseased heart. This review summarizes our current knowledge of the PPARα regulatory mechanisms in cardiac metabolism and the possible role of PPARα in epigenetic modifications in the diseased heart. In addition, we discuss how metabolomics can contribute to a better understanding of the role of PPARα in the progression of cardiac hypertrophy and failure.

scholarly journals Combinatorial Effect of DCA and Let-7a on Triple-Negative MDA-MB-231 Cells: A Metabolic Approach of Treatment

2020 ◽  
Vol 19 ◽  
pp. 153473542091143 ◽  
Author(s):  
Praveen Sharma ◽  
Sandeep Singh
Keyword(s):  
Cancer Cells ◽  
Triple Negative ◽  
Tricarboxylic Acid Cycle ◽  
Combined Treatment ◽  
Reactive Oxygen Species Generation ◽  
Metabolic Reprogramming ◽  
Transcriptional Level ◽  
Cancer Cell Death ◽  
Oxidation Of Glucose

Dichloroacetate (DCA) is a metabolic modulator that inhibits pyruvate dehydrogenase activity and promotes the influx of pyruvate into the tricarboxylic acid cycle for complete oxidation of glucose. DCA stimulates oxidative phosphorylation (OXPHOS) more than glycolysis by altering the morphology of the mitochondria and supports mitochondrial apoptosis. As a consequence, DCA induces apoptosis in cancer cells and inhibits the proliferation of cancer cells. Recently, the role of miRNAs has been reported in regulating gene expression at the transcriptional level and also in reprogramming energy metabolism. In this article, we indicate that DCA treatment leads to the upregulation of let-7a expression, but DCA-induced cancer cell death is independent of let-7a. We observed that the combined effect of DCA and let-7a induces apoptosis, reduces reactive oxygen species generation and autophagy, and stimulates mitochondrial biogenesis. This was later accompanied by stimulation of OXPHOS in combined treatment and was thus involved in metabolic reprogramming of MDA-MB-231 cells.

scholarly journals THE YKI-CACTUS (IKBα)-JNK AXIS PROMOTES TUMOR GROWTH AND PROGRESSION IN DROSOPHILA

2020 ◽  
Author(s):  
Kirti Snigdha ◽  
Amit Singh ◽  
Madhuri Kango-Singh
Keyword(s):  
Tumor Progression ◽  
Tumor Cells ◽  
Critical Role ◽  
Suppressor Gene ◽  
Inflammatory Factors ◽  
Oncogenic Signaling ◽  
Jnk Pathway ◽  
Target Matrix ◽  
Necrosis Factor

AbstractPresence of inflammatory factors in the tumor microenvironment is well known yet their specific role in tumorigenesis is elusive. The core inflammatory pathways are conserved in Drosophila, including the Toll-Like Receptor (TLR) and the Tumor Necrosis Factor (TNF) pathway. We used Drosophila tumor models to study the role of inflammatory factors in tumorigenesis. Specifically, we co-activated oncogenic forms of RasV12 or its major effector Yorkie (Yki3SA) in polarity deficient cells mutant for tumor suppressor gene scribble (scrib) marked by GFP under nubGAL4 or in somatic clones. This system recapitulates the clonal origins of cancer, and shows neoplastic growth, invasion and lethality. We investigated if TLR and TNF pathway affect growth of Yki3SAscribRNAi or RasV12scribRNAi tumors through activation of tumor promoting Jun N-terminal Kinase (JNK) pathway and its target Matrix Metalloprotease1 (MMP1). We report, TLR component, Cactus (Cact) is highly upregulated in Yki3SAscribRNAi or RasV12scribRNAi tumors. Drosophila Cactus (mammalian IKBα) acts as an inhibitor of NFKB signaling that plays key roles in inflammatory and immune response. Here we show an alternative role for Cactus, and by extension cytokine mediated signaling, in tumorigenesis. Downregulating Cact affects both tumor progression and invasion. Interestingly, downregulating TNF receptors in tumor cells did not affect their invasiveness despite reducing JNK activity. Genetic analysis suggested that Cact and JNK are key regulators of tumor progression. Overall, we show that Yki plays a critical role in tumorigenesis by controlling Cact, which in turn, mediates tumor promoting JNK oncogenic signaling in tumor cells.

scholarly journals Macrophage-derived miR-21 drives overwhelming glycolytic and inflammatory response during sepsis via repression of the PGE2/IL-10 axis

2020 ◽  
Author(s):  
Paulo Melo ◽  
Annie Rocio Pineros Alvarez ◽  
C. Henrique Serezani
Keyword(s):  
Inflammatory Response ◽  
Systemic Inflammation ◽  
Inflammatory Mediators ◽  
Aerobic Glycolysis ◽  
Critical Role ◽  
Organ Damage ◽  
Metabolic Reprogramming ◽  
Prostaglandin E ◽  
Anti Inflammatory

AbstractMyeloid cells play a critical role in the development of systemic inflammation and organ damage during sepsis. The mechanisms the development of aberrant inflammatory response remains to be elucidated. MicroRNAs are small non-coding RNAs that could prevent the expression of inflammatory molecules. Although the microRNA-21 (miR-21) is abundantly expressed in macrophages, the role of miR-21 in sepsis is controversial. Here we showed that miR-21 is upregulated in neutrophils and macrophages from septic mice. We found that myeloid-specific miR-21 deletion enhances animal survival, followed by decreased bacterial growth and organ damage during sepsis. Increased resistance against sepsis was associated with a reduction of aerobic glycolysis (as determined by reduced extracellular acidification rate (ECAR) and expression of glycolytic enzymes) and systemic inflammatory response (IL-1βTNFα and IL-6). While miR-21-/- macrophages failed to induce aerobic glycolysis and production of pro-inflammatory cytokines, we observed increased levels of the anti-inflammatory mediators’ prostaglandin E2 (PGE2) and IL10. Using blocking antibodies and pharmacological tools, we further discovered that increased survival and decreased systemic inflammation in miR21Δmyel during sepsis is dependent on the PGE2/IL10-mediated glycolysis inhibition. Together, we are showing a heretofore unknown role of macrophage miR21 in the orchestrating the balance between anti-inflammatory mediators and metabolic reprogramming that drives cytokine storm and tissue damage during sepsis.

scholarly journals TGF-βRII regulates glucose metabolism in oral cancer-associated fibroblasts via promoting PKM2 nuclear translocation

2022 ◽  
Vol 8 (1) ◽  
Author(s):  
Fanglong Wu ◽  
Shimeng Wang ◽  
Qingxiang Zeng ◽  
Junjiang Liu ◽  
Jin Yang ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Oral Cancer ◽  
Nuclear Translocation ◽  
Aerobic Glycolysis ◽  
Critical Role ◽  
Metabolic Reprogramming ◽  
Cancer Associated Fibroblasts

AbstractCancer-associated fibroblasts (CAFs) are highly heterogeneous and differentiated stromal cells that promote tumor progression via remodeling of extracellular matrix, maintenance of stemness, angiogenesis, and modulation of tumor metabolism. Aerobic glycolysis is characterized by an increased uptake of glucose for conversion into lactate under sufficient oxygen conditions, and this metabolic process occurs at the site of energy exchange between CAFs and cancer cells. As a hallmark of cancer, metabolic reprogramming of CAFs is defined as reverse Warburg effect (RWE), characterized by increased lactate, glutamine, and pyruvate, etc. derived from aerobic glycolysis. Given that the TGF-β signal cascade plays a critical role in RWE mainly through metabolic reprogramming related proteins including pyruvate kinase muscle isozyme 2 (PKM2), however, the role of nuclear PKM2 in modifying glycolysis remains largely unknown. In this study, using a series of in vitro and in vivo experiments, we provide evidence that TGF-βRII overexpression suppresses glucose metabolism in CAFs by attenuating PKM2 nuclear translocation, thereby inhibiting oral cancer tumor growth. This study highlights a novel pathway that explains the role of TGF-βRII in CAFs glucose metabolism and suggests that targeting TGF-βRII in CAFs might represent a therapeutic approach for oral cancer.

scholarly journals Cancer: An Oxidative Crosstalk between Solid Tumor Cells and Cancer Associated Fibroblasts

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Alessandro Arcucci ◽  
Maria Rosaria Ruocco ◽  
Giuseppina Granato ◽  
Anna Maria Sacco ◽  
Stefania Montagnani
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Tumor Progression ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Critical Role ◽  
Metabolic Reprogramming ◽  
Antioxidant Systems ◽  
Activation Process ◽  
Cancer Associated Fibroblasts

Redox balance is associated with the regulation of several cell signalling pathways and functions. In fact, under physiological conditions, cells maintain a balance between oxidant and antioxidant systems, and reactive oxygen species (ROS) can act as second messengers to regulate cell proliferation, cell death, and other physiological processes. Cancer tissues usually contain higher levels of ROS than normal tissues, and this ROS overproduction is associated with tumor development. Neoplastic tissues are very heterogeneous systems, composed of tumor cells and microenvironment that has a critical role in tumor progression. Cancer associated fibroblasts (CAFs) represent the main cell type of tumor microenvironment, and they contribute to tumor growth by undergoing an irreversible activation process. It is known that ROS can be transferred from cancer cells to fibroblasts. In particular, ROS affect the behaviour of CAFs by promoting the conversion of fibroblasts to myofibroblasts that support tumor progression and dissemination. Furthermore, the wrecking of redox homeostasis in cancer cells and tumor microenvironment induces a metabolic reprogramming in tumor cells and cancer associated fibroblasts, giving advantage to cancer growth. This review describes the role of ROS in tumor growth, by focusing on CAFs activation and metabolic interactions between cancer cells and stromal fibroblasts.

scholarly journals Metabolic profiling during malaria reveals the role of the aryl hydrocarbon receptor in regulating kidney injury

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Michelle M Lissner ◽  
Katherine Cumnock ◽  
Nicole M Davis ◽  
José G Vilches-Moure ◽  
Priyanka Basak ◽  
...  
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Metabolic Response ◽  
Acute Infection ◽  
Critical Role ◽  
Kidney Injury ◽  
High Plasma ◽  
Metabolic Reprogramming ◽  
Aryl Hydrocarbon ◽  
Specific Effects

Systemic metabolic reprogramming induced by infection exerts profound, pathogen-specific effects on infection outcome. Here, we detail the host immune and metabolic response during sickness and recovery in a mouse model of malaria. We describe extensive alterations in metabolism during acute infection, and identify increases in host-derived metabolites that signal through the aryl hydrocarbon receptor (AHR), a transcription factor with immunomodulatory functions. We find that Ahr-/- mice are more susceptible to malaria and develop high plasma heme and acute kidney injury. This phenotype is dependent on AHR in Tek-expressing radioresistant cells. Our findings identify a role for AHR in limiting tissue damage during malaria. Furthermore, this work demonstrates the critical role of host metabolism in surviving infection.

scholarly journals Multi-Omics Analysis Defines 5-Fluorouracil Drug Resistance in 3D Hela Carcinoma Cell Model

2021 ◽  
Author(s):  
Lin Wang ◽  
Xueting Wang ◽  
Tong Wang ◽  
Yingping Zhuang ◽  
GUAN WANG
Keyword(s):  
Drug Resistance ◽  
Drug Screening ◽  
Monolayer Culture ◽  
Tricarboxylic Acid Cycle ◽  
Critical Role ◽  
Carcinoma Cells ◽  
Metabolic Reprogramming ◽  
Holistic View ◽  
Ecm Proteins

Abstract Cervical cancer is a serious health problem in women around the globe, with 600 thousand new cases each year. However, the use of clinical drug is seriously dampened by the development of drug resistance, which has been evidenced to be associated with metabolic reprogramming and heterogeneity in tumor cells. Efficient in vitro tumor model is essential to improve the efficiency of drug screening and the accuracy of clinical application. Multicellular tumor spheroids (MTSs) can in a way recapitulates tumor traits in vivo, thereby representing a powerful transitional model between 2D monolayer culture and xenograft. In this study, based on the liquid overlay method, a protocol for rapid generation of the MTSs with uniform size and high reproducibility in a high-throughput manner was established. As expected, the cytotoxicity results showed that there was enhanced 5-FU resistance of HeLa carcinoma cells in 3D MTSs than 2D monolayer culture with a resistance index of 5.72. In the presence of both glucose and glutamine, HeLa carcinoma cells preferentially used glutamine as the bioenergetic substrate to support cell proliferation and maintenance under all conditions, while the ubiquitous by-product ammonium might be only recycled in the 3D MTSs. Furthermore, in order to obtain a holistic view of the molecular mechanisms that drive 5-FU resistance in 3D HeLa carcinoma cells, a multi-omics study was applied to discover hidden biological regularities. It was observed that in the 3D MTSs mitochondrial function-related proteins and the metabolites of the tricarboxylic acid cycle (TCA cycle) were significantly decreased, and the cellular metabolism was shifted towards glycolysis. The differences in the protein synthesis, processing, and transportation between 2D monolayer cultures and 3D MTSs was significant, mainly in the heat shock protein family, with the upregulation of protein folding function in endoplasmic reticulum (ER), which promoted the maintenance of ER homeostasis in the 3D MTSs. In addition, at the transcript and protein level, the expression of extracellular matrix (ECM) proteins (e.g., laminin and collagen) were up-regulated in the 3D MTSs, which enhanced the physical barrier of drug penetration. Summarizing, this study formulates a rapid, scalable and reproducible in vitro model of 3D MTS for drug screening purposes, and the findings establish a critical role of glycolytic metabolism, ER hemostasis and ECM proteins expression profiling in tumor chemoresistance of HeLa carcinoma cells towards 5-FU.

scholarly journals The Crosstalk between Cancer Stem Cells and Microenvironment Is Critical for Solid Tumor Progression: The Significant Contribution of Extracellular Vesicles

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Chiara Ciardiello ◽  
Alessandra Leone ◽  
Alfredo Budillon
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Tumor Progression ◽  
Cell Fate ◽  
Extracellular Vesicles ◽  
Significant Contribution ◽  
Critical Role ◽  
Mediated Communication

Several evidences nowadays demonstrated the critical role of the microenvironment in regulating cancer stem cells and their involvement in tumor progression. Extracellular vesicles (EVs) are considered as one of the most effective vehicles of information among cells. Accordingly, a number of studies led to the recognition of stem cell-associated EVs as new complexes able to contribute to cell fate determination of either normal or tumor cells. In this review, we aim to highlight an existing bidirectional role of EV-mediated communication—from cancer stem cells to microenvironment and also from microenvironment to cancer stem cells—in the most widespread solid cancers as prostate, breast, lung, and colon tumors.

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