More Than Meets the Eye Regarding Cancer Metabolism

In spite of the continuous improvement in our knowledge of the nature of cancer, the causes of its formation and the development of new treatment methods, our knowledge is still incomplete. A key issue is the difference in metabolism between normal and cancer cells. The features that distinguish cancer cells from normal cells are the increased proliferation and abnormal differentiation and maturation of these cells, which are due to regulatory changes in the emerging tumour. Normal cells use oxidative phosphorylation (OXPHOS) in the mitochondrion as a major source of energy during division. During OXPHOS, there are 36 ATP molecules produced from one molecule of glucose, in contrast to glycolysis which provides an ATP supply of only two molecules. Although aerobic glucose metabolism is more efficient, metabolism based on intensive glycolysis provides intermediate metabolites necessary for the synthesis of nucleic acids, proteins and lipids, which are in constant high demand due to the intense cell division in cancer. This is the main reason why the cancer cell does not “give up” on glycolysis despite the high demand for energy in the form of ATP. One of the evolving trends in the development of anti-cancer therapies is to exploit differences in the metabolism of normal cells and cancer cells. Currently constructed therapies, based on cell metabolism, focus on the attempt to reprogram the metabolic pathways of the cell in such a manner that it becomes possible to stop unrestrained proliferation.

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

International Journal of Molecular Sciences ◽

10.3390/ijms22031171 ◽

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.

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Radiosensitizing effects of citrate-coated cobalt and nickel ferrite nanoparticles on breast cancer cells

Nanomedicine ◽

10.2217/nnm-2020-0313 ◽

2020 ◽

Vol 15 (29) ◽

pp. 2823-2836

Author(s):

Daniele A Fagundes ◽

Liliam V Leonel ◽

Luis E Fernandez-Outon ◽

José D Ardisson ◽

Raquel G dos Santos

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Nickel Ferrite ◽

Breast Cancer Cells ◽

Cell Metabolism ◽

Ferrite Nanoparticles ◽

Normal Fibroblast ◽

Normal Cells ◽

Nickel Ferrite Nanoparticles ◽

Cobalt And Nickel

Aim: Evaluation of the biocompatibility and radiosensitizer potential of citrate-coated cobalt (cit-CF) and nickel (cit-NF) ferrite nanoparticles (NPs). Materials & methods: Normal fibroblast and breast cancer cells were treated with different concentrations of citrate-coated ferrite NPs (cit-NPs) and irradiated with a cobalt-60 source at doses of 1 and 3 Gy. After 24 h, cell metabolism, morphology alterations and nanoparticle uptake were evaluated. Results: Cit-CF and cit-NF NPs showed no toxicity to normal cells up to 250 and 100 μg.ml-1, respectively. Combination of cit-NP and ionizing radiation resulted in up to fivefold increase in the radiation therapeutic efficacy against breast cancer cells. Conclusion: Cit-CF and cit-NF NPs are suitable candidates for application as breast cancer cell radiosensitizers.

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A Triple Co-Delivery Liposomal Carrier That Enhances Apoptosis via an Intrinsic Pathway in Melanoma Cells

Cancers ◽

10.3390/cancers11121982 ◽

2019 ◽

Vol 11 (12) ◽

pp. 1982 ◽

Cited By ~ 4

Author(s):

Nina Filipczak ◽

Anna Jaromin ◽

Adriana Piwoni ◽

Mohamed Mahmud ◽

Can Sarisozen ◽

...

Keyword(s):

Cancer Cells ◽

Melanoma Cells ◽

Mitochondrial Pathway ◽

Cytotoxic Action ◽

Cancer Therapies ◽

Normal Cells ◽

Freeze And Thaw ◽

Anti Cancer ◽

Remote Loading ◽

Activity Mechanism

The effectiveness of existing anti-cancer therapies is based mainly on the stimulation of apoptosis of cancer cells. Most of the existing therapies are somewhat toxic to normal cells. Therefore, the quest for nontoxic, cancer-specific therapies remains. We have demonstrated the ability of liposomes containing anacardic acid, mitoxantrone and ammonium ascorbate to induce the mitochondrial pathway of apoptosis via reactive oxygen species (ROS) production by the killing of cancer cells in monolayer culture and shown its specificity towards melanoma cells. Liposomes were prepared by a lipid hydration, freeze-and-thaw (FAT) procedure and extrusion through polycarbonate filters, a remote loading method was used for dug encapsulation. Following characterization, hemolytic activity, cytotoxicity and apoptosis inducing effects of loaded nanoparticles were investigated. To identify the anticancer activity mechanism of these liposomes, ROS level and caspase 9 activity were measured by fluorescence and by chemiluminescence respectively. We have demonstrated that the developed liposomal formulations produced a high ROS level, enhanced apoptosis and cell death in melanoma cells, but not in normal cells. The proposed mechanism of the cytotoxic action of these liposomes involved specific generation of free radicals by the iron ions mechanism.

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

International Journal of Molecular Sciences ◽

10.3390/ijms20153694 ◽

2019 ◽

Vol 20 (15) ◽

pp. 3694 ◽

Cited By ~ 9

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.

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Macrosphelide A Exhibits a Specific Anti-Cancer Effect by Simultaneously Inactivating ENO1, ALDOA, and FH

Pharmaceuticals ◽

10.3390/ph14101060 ◽

2021 ◽

Vol 14 (10) ◽

pp. 1060

Author(s):

Kyoung Song ◽

Nirmal Rajasekaran ◽

Chaithanya Chelakkot ◽

Hunseok Lee ◽

Seungmann Paek ◽

...

Keyword(s):

Cancer Cells ◽

Warburg Effect ◽

Cancer Metabolism ◽

Aerobic Glycolysis ◽

Fumarate Hydratase ◽

Metabolic Adaptation ◽

Normal Cells ◽

Target Proteins ◽

Anti Cancer ◽

The Warburg Effect

Aerobic glycolysis in cancer cells, also known as the Warburg effect, is an indispensable hallmark of cancer. This metabolic adaptation of cancer cells makes them remarkably different from normal cells; thus, inhibiting aerobic glycolysis is an attractive strategy to specifically target tumor cells while sparing normal cells. Macrosphelide A (MSPA), an organic small molecule, is a potential lead compound for the design of anti-cancer drugs. However, its role in modulating cancer metabolism remains poorly understood. MSPA target proteins were screened using mass spectrometry proteomics combined with affinity chromatography. Direct and specific interactions of MSPA with its candidate target proteins were confirmed by in vitro binding assays, competition assays, and simulation modeling. The siRNA-based knockdown of MSPA target proteins indirectly confirmed the cytotoxic effect of MSPA in HepG2 and MCF-7 cancer cells. In addition, we showed that MSPA treatment in the HEPG2 cell line significantly reduced glucose consumption and lactate release. MSPA also inhibited cancer cell proliferation and induced apoptosis by inhibiting critical enzymes involved in the Warburg effect: aldolase A (ALDOA), enolase 1 (ENO1), and fumarate hydratase (FH). Among these enzymes, the purified ENO1 inhibitory potency of MSPA was further confirmed to demonstrate the direct inhibition of enzyme activity to exclude indirect/secondary factors. In summary, MSPA exhibits anti-cancer effects by simultaneously targeting ENO1, ALDOA, and FH.

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Cancer metabolism and intervention therapy

Molecular Biomedicine ◽

10.1186/s43556-020-00012-1 ◽

2021 ◽

Vol 2 (1) ◽

Author(s):

Huakan Zhao ◽

Yongsheng Li

Keyword(s):

Cancer Cells ◽

Tumor Cells ◽

Cancer Metabolism ◽

Aerobic Glycolysis ◽

Acid Synthesis ◽

Pentose Phosphate ◽

Metabolic Reprogramming ◽

Cancer Therapies ◽

Proliferation And Metastasis ◽

Immunosuppressive Microenvironment

AbstractMetabolic reprogramming with heterogeneity is a hallmark of cancer and is at the basis of malignant behaviors. It supports the proliferation and metastasis of tumor cells according to the low nutrition and hypoxic microenvironment. Tumor cells frantically grab energy sources (such as glucose, fatty acids, and glutamine) from different pathways to produce a variety of biomass to meet their material needs via enhanced synthetic pathways, including aerobic glycolysis, glutaminolysis, fatty acid synthesis (FAS), and pentose phosphate pathway (PPP). To survive from stress conditions (e.g., metastasis, irradiation, or chemotherapy), tumor cells have to reprogram their metabolism from biomass production towards the generation of abundant adenosine triphosphate (ATP) and antioxidants. In addition, cancer cells remodel the microenvironment through metabolites, promoting an immunosuppressive microenvironment. Herein, we discuss how the metabolism is reprogrammed in cancer cells and how the tumor microenvironment is educated via the metabolic products. We also highlight potential metabolic targets for cancer therapies.

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Functional polyesters enable selective siRNA delivery to lung cancer over matched normal cells

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1606886113 ◽

2016 ◽

Vol 113 (39) ◽

pp. E5702-E5710 ◽

Cited By ~ 42

Author(s):

Yunfeng Yan ◽

Li Liu ◽

Hu Xiong ◽

Jason B. Miller ◽

Kejin Zhou ◽

...

Keyword(s):

Lung Cancer ◽

Side Effects ◽

Cancer Cells ◽

Drug Carrier ◽

Sirna Delivery ◽

Normal Lung ◽

Cancer Therapies ◽

Normal Cells ◽

Alternative Approach ◽

Dividing Cells

Conventional chemotherapeutics nonselectively kill all rapidly dividing cells, which produces numerous side effects. To address this challenge, we report the discovery of functional polyesters that are capable of delivering siRNA drugs selectively to lung cancer cells and not to normal lung cells. Selective polyplex nanoparticles (NPs) were identified by high-throughput library screening on a unique pair of matched cancer/normal cell lines obtained from a single patient. Selective NPs promoted rapid endocytosis into HCC4017 cancer cells, but were arrested at the membrane of HBEC30-KT normal cells during the initial transfection period. When injected into tumor xenografts in mice, cancer-selective NPs were retained in tumors for over 1 wk, whereas nonselective NPs were cleared within hours. This translated to improved siRNA-mediated cancer cell apoptosis and significant suppression of tumor growth. Selective NPs were also able to mediate gene silencing in xenograft and orthotopic tumors via i.v. injection or aerosol inhalation, respectively. Importantly, this work highlights that different cells respond differentially to the same drug carrier, an important factor that should be considered in the design and evaluation of all NP carriers. Because no targeting ligands are required, these functional polyester NPs provide an exciting alternative approach for selective drug delivery to tumor cells that may improve efficacy and reduce adverse side effects of cancer therapies.

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Effect of Exogenous pH on Cell Growth of Breast Cancer Cells

10.21203/rs.3.rs-260226/v1 ◽

2021 ◽

Author(s):

Sungmun Lee

Keyword(s):

Breast Cancer ◽

Cell Growth ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Cell Metabolism ◽

Acidic Ph ◽

Normal Cells ◽

M Phase ◽

Life Threatening ◽

Acidic Conditions

Abstract Breast cancer is the most common cancer in women and the most life-threatening cancer in women worldwide. One key feature of cancer cells including breast cancer cells is a reversed pH gradient, and extracellular pH (pHe) of cancer cells is more acidic than normal cells. Cancer cells have lower pHe of ~ 6.7–7.1 and higher intracellular pH (pHi) of 7.4, while normal cells have pHe of 7.4 and lower pHi of 7.2. Here, we investigated how exogenous pH affected breast cancer cells. MDA-MB-231 cell lines were cultured in five different pHs, pH 6.0, pH 6.7, pH 7.4, pH 8.4, and pH 9.2 of medium. The cells were growing in pH 6.0 and pH 9.2 however, not as fast as in other pHs. Especially they were floating in more acidic conditions than pH 6.3. In alkaline pH (pH 8.4 and pH 9.2), more cells were early apoptotic and they were in S phase. In acidic pH (pH 6.0), more cells were late apoptotic or necrotic and more cells were at G2/M phase in acidic pH (pH 6.0 and pH 6.7). The results suggested that MDA-MB-231 cells experienced different cell growth and cell metabolism in different pHs.

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AFM Force Relaxation Curve Reveals That the Decrease of Membrane Tension Is the Essential Reason for the Softening of Cancer Cells

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.663021 ◽

2021 ◽

Vol 9 ◽

Author(s):

Keli Ren ◽

Jingwei Gao ◽

Dong Han

Keyword(s):

Cell Membrane ◽

Cancer Cells ◽

Mechanical Characterization ◽

Relaxation Curve ◽

Membrane Tension ◽

Normal Cells ◽

Force Relaxation ◽

The Difference ◽

Relaxation Curves ◽

Main Component

Differences in stiffness constitute an extremely important aspect of the mechanical differences between cancer cells and normal cells, and atomic force microscopy (AFM) is the most commonly used tool to characterize the difference in stiffness. However, the process of mechanical characterization using AFM has been controversial and the influence of the membrane tension on AFM measurement results was often ignored. Here, a physical model involving a simultaneous consideration of the effects of the cell membrane, cytoskeleton network and cytosol was proposed. We carried out a theoretical analysis of AFM force relaxation curves, and as a result solved many of the remaining controversial issues regarding AFM-based mechanical characterization of cells, and provided a quantitative solution for the membrane tension measured using AFM indentation experiments for the first time. From the results of experiments on cells with different adherent shapes and different pairs of normal cells and cancer cells, we found additional force provided by membrane tension to be the main component of the force applied to the AFM probe, with decreased cell membrane tension being the essential reason for the greater softness of cancer cells than of normal cells. Hence, regulating membrane tension may become an important method for regulating the behavior of cancer cells.

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Glucose Transporters as a Target for Anticancer Therapy

Cancers ◽

10.3390/cancers13164184 ◽

2021 ◽

Vol 13 (16) ◽

pp. 4184

Author(s):

Monika Pliszka ◽

Leszek Szablewski

Keyword(s):

Cancer Cells ◽

Cancer Metabolism ◽

Radioiodine Therapy ◽

Hypoxic Condition ◽

Glucose Transporters ◽

Anticancer Therapy ◽

Diagnostic Techniques ◽

Normal Cells ◽

Patients With Cancer ◽

Oxidative Breakdown

Tumor growth causes cancer cells to become hypoxic. A hypoxic condition is a hallmark of cancer. Metabolism of cancer cells differs from metabolism of normal cells. Cancer cells prefer the process of glycolysis as a source of ATP. Process of glycolysis generates only two molecules of ATP per one molecule of glucose, whereas the complete oxidative breakdown of one molecule of glucose yields 36 molecules of ATP. Therefore, cancer cells need more molecules of glucose in comparison with normal cells. Increased uptake of glucose by these cells is due to overexpression of glucose transporters, especially GLUT1 and GLUT3, that are hypoxia responsive, as well as other glucose transport proteins. Increased expression of these carrier proteins may be used in anticancer therapy. This phenomenon is used in diagnostic techniques such as FDG-PET. It is also suggested, and there are observations, that therapeutic inhibition of glucose transporters may be a method in treatment of cancer patients. On the other hand, there are described cases, in which upregulation of glucose transporters, as, for example, NIS, which is used in radioiodine therapy, can help patients with cancer. The aim of this review is the presentation of possibilities, and how glucose transporters can be used in anticancer therapy.

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