scholarly journals Oncogene inference optimization using constraint-based modelling incorporated with protein expression in normal and tumour tissues

2020 ◽  
Vol 7 (3) ◽  
pp. 191241
Author(s):  
Wu-Hsiung Wu ◽  
Fan-Yu Li ◽  
Yi-Chen Shu ◽  
Jin-Mei Lai ◽  
Peter Mu-Hsin Chang ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Optimization Problem ◽  
Human Cancer ◽  
Cell Metabolism ◽  
Differential Evolution Algorithm ◽  
Network Models ◽  
Genetic Alterations ◽  
Metabolic Reprogramming ◽  
Tumour Suppressor Genes ◽  
Driver Genes

Cancer cells are known to exhibit unusual metabolic activity, and yet few metabolic cancer driver genes are known. Genetic alterations and epigenetic modifications of cancer cells result in the abnormal regulation of cellular metabolic pathways that are different when compared with normal cells. Such a metabolic reprogramming can be simulated using constraint-based modelling approaches towards predicting oncogenes. We introduced the tri-level optimization problem to use the metabolic reprogramming towards inferring oncogenes. The algorithm incorporated Recon 2.2 network with the Human Protein Atlas to reconstruct genome-scale metabolic network models of the tissue-specific cells at normal and cancer states, respectively. Such reconstructed models were applied to build the templates of the metabolic reprogramming between normal and cancer cell metabolism. The inference optimization problem was formulated to use the templates as a measure towards predicting oncogenes. The nested hybrid differential evolution algorithm was applied to solve the problem to overcome solving difficulty for transferring the inner optimization problem into the single one. Head and neck squamous cells were applied as a case study to evaluate the algorithm. We detected 13 of the top-ranked one-hit dysregulations and 17 of the top-ranked two-hit oncogenes with high similarity ratios to the templates. According to the literature survey, most inferred oncogenes are consistent with the observation in various tissues. Furthermore, the inferred oncogenes were highly connected with the TP53/AKT/IGF/MTOR signalling pathway through PTEN, which is one of the most frequently detected tumour suppressor genes in human cancer.

scholarly journals Targeting Redox Metabolism in Pancreatic Cancer

2021 ◽  
Vol 22 (4) ◽  
pp. 1534
Author(s):  
Nadine Abdel Hadi ◽  
Gabriela Reyes-Castellanos ◽  
Alice Carrier
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Cell Metabolism ◽  
Genetic Alterations ◽  
Metabolic Reprogramming ◽  
Antioxidant Defenses ◽  
Ductal Adenocarcinoma ◽  
Ros Production ◽  
High Concentration ◽  
Redox Metabolism

Cell metabolism is reprogrammed in cancer cells to meet their high bioenergetics and biosynthetic demands. This metabolic reprogramming is accompanied by alterations in redox metabolism, characterized by accumulation of reactive oxygen species (ROS). Elevated production of ROS, mostly by mitochondrial respiration, is counteracted by higher production of antioxidant defenses (mainly glutathione and antioxidant enzymes). Cancer cells are adapted to a high concentration of ROS, which contributes to tumorigenesis, metastasis formation, resistance to therapy and relapse. Frequent genetic alterations observed in pancreatic ductal adenocarcinoma (PDAC) affect KRAS and p53 proteins, which have a role in ROS production and control, respectively. These observations led to the proposal of the use of antioxidants to prevent PDAC development and relapse. In this review, we focus on the therapeutic strategies to further increase ROS level to induce PDAC cell death. Combining the promotion of ROS production and inhibition of antioxidant capacity is a promising avenue for pancreatic cancer therapy in the clinic.

scholarly journals The Role of PKM2 in Metabolic Reprogramming: Insights into the Regulatory Roles of Non-Coding RNAs

2021 ◽  
Vol 22 (3) ◽  
pp. 1171
Author(s):  
Dexter L. Puckett ◽  
Mohammed Alquraishi ◽  
Winyoo Chowanadisai ◽  
Ahmed Bettaieb
Keyword(s):  
Cancer Cells ◽  
Pyruvate Kinase ◽  
Cancer Metabolism ◽  
Cell Metabolism ◽  
Metabolic Reprogramming ◽  
Circular Rnas ◽  
Tissue Specific ◽  
Cell Progression ◽  
Non Coding Rnas ◽  
Regulatory Effects

Pyruvate kinase is a key regulator in glycolysis through the conversion of phosphoenolpyruvate (PEP) into pyruvate. Pyruvate kinase exists in various isoforms that can exhibit diverse biological functions and outcomes. The pyruvate kinase isoenzyme type M2 (PKM2) controls cell progression and survival through the regulation of key signaling pathways. In cancer cells, the dimer form of PKM2 predominates and plays an integral role in cancer metabolism. This predominance of the inactive dimeric form promotes the accumulation of phosphometabolites, allowing cancer cells to engage in high levels of synthetic processing to enhance their proliferative capacity. PKM2 has been recognized for its role in regulating gene expression and transcription factors critical for health and disease. This role enables PKM2 to exert profound regulatory effects that promote cancer cell metabolism, proliferation, and migration. In addition to its role in cancer, PKM2 regulates aspects essential to cellular homeostasis in non-cancer tissues and, in some cases, promotes tissue-specific pathways in health and diseases. In pursuit of understanding the diverse tissue-specific roles of PKM2, investigations targeting tissues such as the kidney, liver, adipose, and pancreas have been conducted. Findings from these studies enhance our understanding of PKM2 functions in various diseases beyond cancer. Therefore, there is substantial interest in PKM2 modulation as a potential therapeutic target for the treatment of multiple conditions. Indeed, a vast plethora of research has focused on identifying therapeutic strategies for targeting PKM2. Recently, targeting PKM2 through its regulatory microRNAs, long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) has gathered increasing interest. Thus, the goal of this review is to highlight recent advancements in PKM2 research, with a focus on PKM2 regulatory microRNAs and lncRNAs and their subsequent physiological significance.

The F1Fo-ATPase inhibitor, IF1, is a critical regulator of energy metabolism in cancer cells

2021 ◽  
Vol 49 (2) ◽  
pp. 815-827
Author(s):  
Giancarlo Solaini ◽  
Gianluca Sgarbi ◽  
Alessandra Baracca
Keyword(s):  
Cancer Cells ◽  
Atp Synthase ◽  
Aerobic Glycolysis ◽  
Cell Metabolism ◽  
Metabolic Reprogramming ◽  
Endogenous Inhibitor ◽  
Atpase Inhibitor ◽  
Molecular Action ◽  
F1fo Atpase

In the last two decades, IF1, the endogenous inhibitor of the mitochondrial F1Fo-ATPase (ATP synthase) has assumed greater and ever greater interest since it has been found to be overexpressed in many cancers. At present, several findings indicate that IF1 is capable of playing a central role in cancer cells by promoting metabolic reprogramming, proliferation and resistance to cell death. However, the mechanism(s) at the basis of this pro-oncogenic action of IF1 remains elusive. Here, we recall the main features of the mechanism of the action of IF1 when the ATP synthase works in reverse, and discuss the experimental evidence that support its relevance in cancer cells. In particular, a clear pro-oncogenic action of IF1 is to avoid wasting of ATP when cancer cells are exposed to anoxia or near anoxia conditions, therefore favoring cell survival and tumor growth. However, more recently, various papers have described IF1 as an inhibitor of the ATP synthase when it is working physiologically (i.e. synthethizing ATP), and therefore reprogramming cell metabolism to aerobic glycolysis. In contrast, other studies excluded IF1 as an inhibitor of ATP synthase under normoxia, providing the basis for a hot debate. This review focuses on the role of IF1 as a modulator of the ATP synthase in normoxic cancer cells with the awareness that the knowledge of the molecular action of IF1 on the ATP synthase is crucial in unravelling the molecular mechanism(s) responsible for the pro-oncogenic role of IF1 in cancer and in developing related anticancer strategies.

scholarly journals Inhibition of NADPH Oxidases Activity by Diphenyleneiodonium Chloride as a Mechanism of Senescence Induction in Human Cancer Cells

Antioxidants ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 1248
Author(s):  
Katarzyna Piszczatowska ◽  
Dorota Przybylska ◽  
Ewa Sikora ◽  
Grażyna Mosieniak
Keyword(s):  
Cancer Cells ◽  
Therapeutic Potential ◽  
Human Cancer ◽  
Cell Metabolism ◽  
Human Colon ◽  
Nadph Oxidases ◽  
Human Colon Cancer ◽  
Inhibition Of Proliferation ◽  
Human Cancer Cells ◽  
Mcf 7

NADPH oxidases (NOX) are commonly expressed ROS-producing enzymes that participate in the regulation of many signaling pathways, which influence cell metabolism, survival, and proliferation. Due to their high expression in several different types of cancer it was postulated that NOX promote tumor progression, growth, and survival. Thus, the inhibition of NOX activity was considered to have therapeutic potential. One of the possible outcomes of anticancer therapy, which has recently gained much interest, is cancer cell senescence. The induction of senescence leads to prolonged inhibition of proliferation and contributes to tumor growth restriction. The aim of our studies was to investigate the influence of low, non-toxic doses of diphenyleneiodonium chloride (DPI), a potent inhibitor of flavoenzymes including NADPH oxidases, on p53-proficient and p53-deficient HCT116 human colon cancer cells and MCF-7 breast cancer cells. We demonstrated that the temporal treatment of HCT116 and MCF-7 cancer cells (both p53 wild-type) with DPI caused induction of senescence, that was correlated with decreased level of ROS and upregulation of p53/p21 proteins. On the contrary, in the case of p53−/− HCT116 cells, apoptosis was shown to be the prevailing effect of DPI treatment. Thus, our studies provided a proof that inhibiting ROS production, and by this means influencing ROS sensitive pathways, remains an alternative strategy to facilitate so called therapy-induced senescence in cancers.

scholarly journals Oncogenic KRAS Drives Metabolic Vulnerabilities by Directly Regulating Metabolic Enzymes in Cancer

2020 ◽  
Vol 07 (01) ◽  
pp. 001-002
Author(s):  
Liyi Zhang
Keyword(s):  
Cancer Cells ◽  
Splice Variants ◽  
Human Cancer ◽  
Aerobic Glycolysis ◽  
Metabolic Enzymes ◽  
Glycolytic Enzyme ◽  
Metabolic Reprogramming ◽  
Functional Differences ◽  
Oncogenic Mutations ◽  
Novel Therapeutic Strategies

AbstractMetabolic reprogramming, such as enhanced aerobic glycolysis, allows cancer cells to maintain viability and promote proliferation. It is one of the major consequences of oncogenic mutations. KRAS is the most frequently mutated oncogene in human cancer. It is thought to be closely related to metabolic reprogramming. However, it is not clear whether it can participate in metabolic reprogramming by directly regulating metabolic enzymes. Additionally, the functional differences among the splice variants of KRAS have not been determined. In a study, recently published in Nature, Amendola et al reported a unique interaction between one of the KRAS splice variants (KRAS4A) and the major glycolytic enzyme (hexokinase 1) in cancer cells. Their findings indicated that a better understanding on the regulation of hexokinase 1 by KRAS may reveal novel therapeutic strategies.

scholarly journals The Role of Sodium Hydrogen Exchanger 1 in Dysregulation of Proton Dynamics and Reprogramming of Cancer Metabolism as a Sequela

2019 ◽  
Vol 20 (15) ◽  
pp. 3694 ◽  
Author(s):  
Rosa Cardone ◽  
Khalid Alfarouk ◽  
Robert Elliott ◽  
Saad Alqahtani ◽  
Samrein Ahmed ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cell Biology ◽  
Cancer Metabolism ◽  
Cellular Proliferation ◽  
Cell Metabolism ◽  
Krebs Cycle ◽  
Building Blocks ◽  
Metabolic Reprogramming ◽  
Metabolic Adaptation ◽  
Sodium Hydrogen Exchanger

Cancer cells have an unusual regulation of hydrogen ion dynamics that are driven by poor vascularity perfusion, regional hypoxia, and increased glycolysis. All these forces synergize/orchestrate together to create extracellular acidity and intracellular alkalinity. Precisely, they lead to extracellular pH (pHe) values as low as 6.2 and intracellular pH values as high as 8. This unique pH gradient (∆pHi to ∆pHe) across the cell membrane increases as the tumor progresses, and is markedly displaced from the electrochemical equilibrium of protons. These unusual pH dynamics influence cancer cell biology, including proliferation, metastasis, and metabolic adaptation. Warburg metabolism with increased glycolysis, even in the presence of Oxygen with the subsequent reduction in Krebs’ cycle, is a common feature of most cancers. This metabolic reprogramming confers evolutionary advantages to cancer cells by enhancing their resistance to hypoxia, to chemotherapy or radiotherapy, allowing rapid production of biological building blocks that support cellular proliferation, and shielding against damaging mitochondrial free radicals. In this article, we highlight the interconnected roles of dysregulated pH dynamics in cancer initiation, progression, adaptation, and in determining the programming and re-programming of tumor cell metabolism.

scholarly journals Mitochondrial VDAC1 Silencing Leads to Metabolic Rewiring and the Reprogramming of Tumour Cells into Advanced Differentiated States

Cancers ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 499 ◽  
Author(s):  
Tasleem Arif ◽  
Avijit Paul ◽  
Yakov Krelin ◽  
Anna Shteinfer-Kuzmine ◽  
Varda Shoshan-Barmatz
Keyword(s):  
Lung Cancer ◽  
Cell Differentiation ◽  
Cell Growth ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Tumour Growth ◽  
Cell Metabolism ◽  
Metabolic Reprogramming ◽  
Residual Tumour ◽  
Cancer Cell Metabolism

Oncogenic properties, along with the metabolic reprogramming necessary for tumour growth and motility, are acquired by cancer cells. Thus, tumour metabolism is becoming a target for cancer therapy. Here, cancer cell metabolism was tackled by silencing the expression of voltage-dependent anion channel 1 (VDAC1), a mitochondrial protein that controls cell energy, as well as metabolic and survival pathways and that is often over-expressed in many cancers. We demonstrated that silencing VDAC1 expression using human-specific siRNA (si-hVDAC1) inhibited cancer cell growth, both in vitro and in mouse xenograft models of human glioblastoma (U-87MG), lung cancer (A549), and triple negative breast cancer (MDA-MB-231). Importantly, treatment with si-hVDAC1 induced metabolic rewiring of the cancer cells, reversing their oncogenic properties and diverting them towards differentiated-like cells. The si-hVDAC1-treated residual “tumour” showed reprogrammed metabolism, decreased proliferation, inhibited stemness and altered expression of genes and proteins, leading to cell differentiation toward less malignant lineages. These VDAC1 depletion-mediated effects involved alterations in master transcription factors associated with cancer hallmarks, such as highly increased expression of p53 and decreased expression of HIF-1a and c-Myc that regulate signalling pathways (e.g., AMPK, mTOR). High expression of p53 and the pro-apoptotic proteins cytochrome c and caspases without induction of apoptosis points to functions for these proteins in promoting cell differentiation. These results clearly show that VDAC1 depletion similarly leads to a rewiring of cancer cell metabolism in breast and lung cancer and glioblastoma, regardless of origin or mutational status. This metabolic reprogramming results in cell growth arrest and inhibited tumour growth while encouraging cell differentiation, thus generating cells with decreased proliferation capacity. These results further suggest VDAC1 to be an innovative and markedly potent therapeutic target.

scholarly journals Cancer Cell Metabolism in Hypoxia: Role of HIF-1 as Key Regulator and Therapeutic Target

2021 ◽  
Vol 22 (11) ◽  
pp. 5703
Author(s):  
Vittoria Infantino ◽  
Anna Santarsiero ◽  
Paolo Convertini ◽  
Simona Todisco ◽  
Vito Iacobazzi
Keyword(s):  
Cancer Cells ◽  
Energy Demand ◽  
Molecular Mechanisms ◽  
Cell Metabolism ◽  
Hypoxia Inducible Factor ◽  
Cancer Therapeutics ◽  
High Energy ◽  
Metabolic Reprogramming ◽  
Low Oxygen ◽  
Functional Changes

In order to meet the high energy demand, a metabolic reprogramming occurs in cancer cells. Its role is crucial in promoting tumor survival. Among the substrates in demand, oxygen is fundamental for bioenergetics. Nevertheless, tumor microenvironment is frequently characterized by low-oxygen conditions. Hypoxia-inducible factor 1 (HIF-1) is a pivotal modulator of the metabolic reprogramming which takes place in hypoxic cancer cells. In the hub of cellular bioenergetics, mitochondria are key players in regulating cellular energy. Therefore, a close crosstalk between mitochondria and HIF-1 underlies the metabolic and functional changes of cancer cells. Noteworthy, HIF-1 represents a promising target for novel cancer therapeutics. In this review, we summarize the molecular mechanisms underlying the interplay between HIF-1 and energetic metabolism, with a focus on mitochondria, of hypoxic cancer cells.

scholarly journals The Interplay of Dysregulated pH and Electrolyte Imbalance in Cancer

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 898 ◽  
Author(s):  
Khalid O. Alfarouk ◽  
Samrein B. M. Ahmed ◽  
Ahmed Ahmed ◽  
Robert L. Elliott ◽  
Muntaser E. Ibrahim ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cell Biology ◽  
Cell Transformation ◽  
Aerobic Glycolysis ◽  
Cell Metabolism ◽  
Lactic Acid Production ◽  
Metabolic Reprogramming ◽  
Electrolyte Imbalance ◽  
Vascular Perfusion ◽  
Extracellular Acidosis

Cancer cells and tissues have an aberrant regulation of hydrogen ion dynamics driven by a combination of poor vascular perfusion, regional hypoxia, and increased the flux of carbons through fermentative glycolysis. This leads to extracellular acidosis and intracellular alkalinization. Dysregulated pH dynamics influence cancer cell biology, from cell transformation and tumorigenesis to proliferation, local growth, invasion, and metastasis. Moreover, this dysregulated intracellular pH (pHi) drives a metabolic shift to increased aerobic glycolysis and reduced mitochondrial oxidative phosphorylation, referred to as the Warburg effect, or Warburg metabolism, which is a selective feature of cancer. This metabolic reprogramming confers a thermodynamic advantage on cancer cells and tissues by protecting them against oxidative stress, enhancing their resistance to hypoxia, and allowing a rapid conversion of nutrients into biomass to enable cell proliferation. Indeed, most cancers have increased glucose uptake and lactic acid production. Furthermore, cancer cells have very dysregulated electrolyte balances, and in the interaction of the pH dynamics with electrolyte, dynamics is less well known. In this review, we highlight the interconnected roles of dysregulated pH dynamics and electrolytes imbalance in cancer initiation, progression, adaptation, and in determining the programming and reprogramming of tumor cell metabolism.

scholarly journals Nuclear Translocation of Glutaminase GLS2 in Human Cancer Cells Associates with Proliferation Arrest and Differentiation

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Amada R. López de la Oliva ◽  
José A. Campos-Sandoval ◽  
María C. Gómez-García ◽  
Carolina Cardona ◽  
Mercedes Martín-Rufián ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Tumor Suppressor ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
Human Cancer ◽  
Metabolic Reprogramming ◽  
Nuclear Targeting ◽  
Human Cancer Cells ◽  
Cycle Arrest

AbstractGlutaminase (GA) catalyzes the first step in mitochondrial glutaminolysis playing a key role in cancer metabolic reprogramming. Humans express two types of GA isoforms: GLS and GLS2. GLS isozymes have been consistently related to cell proliferation, but the role of GLS2 in cancer remains poorly understood. GLS2 is repressed in many tumor cells and a better understanding of its function in tumorigenesis may further the development of new therapeutic approaches. We analyzed GLS2 expression in HCC, GBM and neuroblastoma cells, as well as in monkey COS-7 cells. We studied GLS2 expression after induction of differentiation with phorbol ester (PMA) and transduction with the full-length cDNA of GLS2. In parallel, we investigated cell cycle progression and levels of p53, p21 and c-Myc proteins. Using the baculovirus system, human GLS2 protein was overexpressed, purified and analyzed for posttranslational modifications employing a proteomics LC-MS/MS platform. We have demonstrated a dual targeting of GLS2 in human cancer cells. Immunocytochemistry and subcellular fractionation gave consistent results demonstrating nuclear and mitochondrial locations, with the latter being predominant. Nuclear targeting was confirmed in cancer cells overexpressing c-Myc- and GFP-tagged GLS2 proteins. We assessed the subnuclear location finding a widespread distribution of GLS2 in the nucleoplasm without clear overlapping with specific nuclear substructures. GLS2 expression and nuclear accrual notably increased by treatment of SH-SY5Y cells with PMA and it correlated with cell cycle arrest at G2/M, upregulation of tumor suppressor p53 and p21 protein. A similar response was obtained by overexpression of GLS2 in T98G glioma cells, including downregulation of oncogene c-Myc. Furthermore, human GLS2 was identified as being hypusinated by MS analysis, a posttranslational modification which may be relevant for its nuclear targeting and/or function. Our studies provide evidence for a tumor suppressor role of GLS2 in certain types of cancer. The data imply that GLS2 can be regarded as a highly mobile and multilocalizing protein translocated to both mitochondria and nuclei. Upregulation of GLS2 in cancer cells induced an antiproliferative response with cell cycle arrest at the G2/M phase.

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