AMP-Activated Protein Kinase and Cancer Cell Metabolism

Our findings provide comprehensive evidence that isoquercitrin (ISO) influenced T24 bladder cancer cell metabolism by activating the AMPK pathway as identified by combination with metabolomics and immunoblotting assay.

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Metabolic Heterogeneity of Cancer Cells: An Interplay between Reprogrammed and Oxidative Metabolism and Roles of HIF-1, GLUTs and AMPK

10.20944/preprints202002.0436.v1 ◽

2020 ◽

Author(s):

Nurbubu T. Moldogazieva ◽

Innokenty M. Mokhosoev ◽

Alexander A. Terentiev

Keyword(s):

Cancer Cells ◽

Cancer Cell ◽

Oxidative Metabolism ◽

Cell Metabolism ◽

Hypoxia Inducible Factor ◽

Metabolic Plasticity ◽

Anti Cancer ◽

Cancer Cell Metabolism ◽

Metabolic Heterogeneity ◽

Amp Activated Protein Kinase

It has been long recognized that under hypoxia conditions cancer cells reprogram their metabolism through shift from oxidative phosphorylation (OXPHOS) to glycolysis to meet elevated requirements in energy and nutrients for proliferation, migration and survival. However, data accumulated over the last years increasingly evidence that cancer cells can revert from glycolysis to OXPHOS and maintain both reprogrammed and oxidative metabolism even in the same tumor. The phenomenon denoted as cancer cell metabolic plasticity or hybrid metabolism depends on a tumor micro-environment, which is highly heterogeneous and influenced by intensity of vasculature and blood flow, oxygen concentration, nutrient and energy supply, and requires regulatory interplay between multiple oncogenes, transcription factors, growth factors, reactive oxygen species (ROS), etc. Hypoxia-inducible factor-1 (HIF-1) and AMP-activated protein kinase (AMPK) represent key modulators of switch between reprogrammed and oxidative metabolism. The present review focuses on cross-talks between HIF-1, GLUTs, and AMPK and other regulatory proteins including oncogenes such as c-Myc, p53 and KRAS, growth factor-initiated PKB/Akt, PI3K and mTOR signaling pathways and tumor suppressors such as LKB1 and TSC1 in controlling cancer cell metabolism. The multiple switches between metabolic pathways can underlie chemo-resistance to conventional anti-cancer therapy and should be taken into account in choosing molecular targets to discovery novel anti-cancer drugs.

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Metabolic Heterogeneity of Cancer Cells: An Interplay between HIF-1, GLUTs, and AMPK

Cancers ◽

10.3390/cancers12040862 ◽

2020 ◽

Vol 12 (4) ◽

pp. 862 ◽

Cited By ~ 12

Author(s):

Nurbubu T. Moldogazieva ◽

Innokenty M. Mokhosoev ◽

Alexander A. Terentiev

Keyword(s):

Protein Kinase ◽

Cancer Cells ◽

Cancer Cell ◽

Oxidative Metabolism ◽

Cell Metabolism ◽

Hypoxia Inducible Factor ◽

Anti Cancer ◽

Liver Kinase B1 ◽

Metabolic Heterogeneity ◽

Amp Activated Protein Kinase

It has been long recognized that cancer cells reprogram their metabolism under hypoxia conditions due to a shift from oxidative phosphorylation (OXPHOS) to glycolysis in order to meet elevated requirements in energy and nutrients for proliferation, migration, and survival. However, data accumulated over recent years has increasingly provided evidence that cancer cells can revert from glycolysis to OXPHOS and maintain both reprogrammed and oxidative metabolism, even in the same tumor. This phenomenon, denoted as cancer cell metabolic plasticity or hybrid metabolism, depends on a tumor micro-environment that is highly heterogeneous and influenced by an intensity of vasculature and blood flow, oxygen concentration, and nutrient and energy supply, and requires regulatory interplay between multiple oncogenes, transcription factors, growth factors, and reactive oxygen species (ROS), among others. Hypoxia-inducible factor-1 (HIF-1) and AMP-activated protein kinase (AMPK) represent key modulators of a switch between reprogrammed and oxidative metabolism. The present review focuses on cross-talks between HIF-1, glucose transporters (GLUTs), and AMPK with other regulatory proteins including oncogenes such as c-Myc, p53, and KRAS; growth factor-initiated protein kinase B (PKB)/Akt, phosphatidyl-3-kinase (PI3K), and mTOR signaling pathways; and tumor suppressors such as liver kinase B1 (LKB1) and TSC1 in controlling cancer cell metabolism. The multiple switches between metabolic pathways can underlie chemo-resistance to conventional anti-cancer therapy and should be taken into account in choosing molecular targets to discover novel anti-cancer drugs.

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Depletion of dAKAP1–protein kinase A signaling islands from the outer mitochondrial membrane alters breast cancer cell metabolism and motility

Journal of Biological Chemistry ◽

10.1074/jbc.ra118.006741 ◽

2018 ◽

Vol 294 (9) ◽

pp. 3152-3168 ◽

Cited By ~ 8

Author(s):

Stacey Aggarwal ◽

Laura Gabrovsek ◽

Lorene K. Langeberg ◽

Martin Golkowski ◽

Shao-En Ong ◽

...

Keyword(s):

Breast Cancer ◽

Protein Kinase ◽

Protein Kinase A ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Mitochondrial Membrane ◽

Cell Metabolism ◽

Outer Mitochondrial Membrane ◽

Cancer Cell Metabolism ◽

Kinase A

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A New Twist in Protein Kinase B/Akt Signaling: Role of Altered Cancer Cell Metabolism in Akt-Mediated Therapy Resistance

International Journal of Molecular Sciences ◽

10.3390/ijms21228563 ◽

2020 ◽

Vol 21 (22) ◽

pp. 8563 ◽

Cited By ~ 1

Author(s):

Isabell Götting ◽

Verena Jendrossek ◽

Johann Matschke

Keyword(s):

Dna Damage ◽

Protein Kinase ◽

Cancer Cells ◽

Cancer Cell ◽

Protein Kinase B ◽

Cell Metabolism ◽

Therapy Resistance ◽

Dsb Repair ◽

Target Proteins ◽

Cancer Cell Metabolism

Cancer resistance to chemotherapy, radiotherapy and molecular-targeted agents is a major obstacle to successful cancer therapy. Herein, aberrant activation of the phosphatidyl-inositol-3-kinase (PI3K)/protein kinase B (Akt) pathway is one of the most frequently deregulated pathways in cancer cells and has been associated with multiple aspects of therapy resistance. These include, for example, survival under stress conditions, apoptosis resistance, activation of the cellular response to DNA damage and repair of radiation-induced or chemotherapy-induced DNA damage, particularly DNA double strand breaks (DSB). One further important, yet not much investigated aspect of Akt-dependent signaling is the regulation of cell metabolism. In fact, many Akt target proteins are part of or involved in the regulation of metabolic pathways. Furthermore, recent studies revealed the importance of certain metabolites for protection against therapy-induced cell stress and the repair of therapy-induced DNA damage. Thus far, the likely interaction between deregulated activation of Akt, altered cancer metabolism and therapy resistance is not yet well understood. The present review describes the documented interactions between Akt, its target proteins and cancer cell metabolism, focusing on antioxidant defense and DSB repair. Furthermore, the review highlights potential connections between deregulated Akt, cancer cell metabolism and therapy resistance of cancer cells through altered DSB repair and discusses potential resulting therapeutic implications.

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A Holistic Evolutionary and 3D Pharmacophore Modelling Study Provides Insights into the Metabolism, Function, and Substrate Selectivity of the Human Monocarboxylate Transporter 4 (hMCT4)

International Journal of Molecular Sciences ◽

10.3390/ijms22062918 ◽

2021 ◽

Vol 22 (6) ◽

pp. 2918

Author(s):

Eleni Papakonstantinou ◽

Dimitrios Vlachakis ◽

Trias Thireou ◽

Panayiotis G. Vlachoyiannopoulos ◽

Elias Eliopoulos

Keyword(s):

Cancer Cell ◽

Structural Characteristics ◽

Cell Metabolism ◽

Intracellular Localization ◽

Selective Inhibition ◽

Monocarboxylate Transporter ◽

Cancer Drug ◽

Pharmacophore Modelling ◽

Anti Cancer ◽

Cancer Cell Metabolism

Monocarboxylate transporters (MCTs) are of great research interest for their role in cancer cell metabolism and their potential ability to transport pharmacologically relevant compounds across the membrane. Each member of the MCT family could potentially provide novel therapeutic approaches to various diseases. The major differences among MCTs are related to each of their specific metabolic roles, their relative substrate and inhibitor affinities, the regulation of their expression, their intracellular localization, and their tissue distribution. MCT4 is the main mediator for the efflux of L-lactate produced in the cell. Thus, MCT4 maintains the glycolytic phenotype of the cancer cell by supplying the molecular resources for tumor cell proliferation and promotes the acidification of the extracellular microenvironment from the co-transport of protons. A promising therapeutic strategy in anti-cancer drug design is the selective inhibition of MCT4 for the glycolytic suppression of solid tumors. A small number of studies indicate molecules for dual inhibition of MCT1 and MCT4; however, no selective inhibitor with high-affinity for MCT4 has been identified. In this study, we attempt to approach the structural characteristics of MCT4 through an in silico pipeline for molecular modelling and pharmacophore elucidation towards the identification of specific inhibitors as a novel anti-cancer strategy.

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Oncolytic Virotherapy: The Cancer Cell Side

Cancers ◽

10.3390/cancers13050939 ◽

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.

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