Cancer cells recovering from damage exhibit mitochondrial restructuring and increased aerobic glycolysis

Akakura, Shin; Ostrakhovitch, Elena A.; Sanokawa-Akakura, Reiko; Tabibzadeh, Siamak

doi:10.1016/j.bbrc.2014.04.138

Cited by 9 publications

(11 citation statements)

References 22 publications

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“…It was shown that drug resistance is directly proportional to tumor size [50]. Consistent with this, our recently reported findings demonstrated that DR cells inoculated to immunodeficient mice formed larger tumors than those produced by Pc cells within the same time frame [32]. These data indicate that DR cells which show increased drug resistance associated with expression of stem cell markers are more tumorigenic as compared to their parental counterpart cells.…”

Section: Discussionsupporting

confidence: 73%

“…Recently, we reported that cancer cells that recover from a potentially lethal damage display mitochondrial reorganization and increased drug resistance [32] similar to that which is found in induced pluripotent stem cells (iPS). Here, we demonstrate that upon recovery from a potentially lethal damage induced by oxidative stress, hypoxia, or glucose deprivation, cancer cells undergo dedifferentiation characterized by reactivation of expression of a repertoire of stem cell genes and plasticity to transdifferentiate into another cell phenotype.…”

Section: Introductionmentioning

confidence: 91%

“…The isolation of viable tumor (T V ) cells and damaged (T DR ) tumor cells was followed as described in our previous study [32]. Within 1 week, similar to in vitro generated DR cells, T DR cells formed 3D spheroid (T Sp ) structures along with a monolayer of cells (Fig.…”

Section: Accumulation Of H 2 S Leads To the Dedifferentiation Of Cancmentioning

confidence: 99%

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Dedifferentiation of cancer cells following recovery from a potentially lethal damage is mediated by H2S–Nampt

Ostrakhovitch

Akakura

Sanokawa-Akakura

et al. 2015

Experimental Cell Research

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Recently, we reported that cancer cells that recover from a potentially lethal damage gain new phenotypic features comprised of mitochondrial structural remodeling associated with increased glycolytic dependency and drug resistance. Here, we demonstrate that a subset of cancer cells, upon recovery from a potentially lethal damage, undergo dedifferentiation and express genes, which are characteristic of undifferentiated stem cells. While these cells are competent in maintaining differentiated progeny of tumor, they also exhibit transdifferentiation potential. Dedifferentiation is characterized by accumulation of hydrogen sulfide (H2S), which triggers up-regulation of nicotinamide phosphoribosyltransferase (Nampt) accompanied by changes in the redox state. The molecular events triggered by Nampt include elevated production of NAD(+) and up-regulation of H2S producing enzymes, cystathionine beta synthase (CBS) and cystathionase (CTH) with 3-mercaptopyruvate sulfurtransferase (MST) being detectable only in 3D spheroids. Suppression of Nampt, or inactivation of H2S producing enzymes, all reduce H2S production and reverse the ability of cells to dedifferentiate. Moreover, H2S induced stem cell markers in parental cancer cells in a manner similar to that observed in damage recovered cells. These data suggest of existence of a positive feedback loop between H2S and Nampt that controls dedifferentiation in cancer cells that recover from a potentially lethal damage.

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Section: Discussionsupporting

confidence: 73%

Section: Introductionmentioning

confidence: 91%

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Dedifferentiation of cancer cells following recovery from a potentially lethal damage is mediated by H2S–Nampt

Ostrakhovitch

Akakura

Sanokawa-Akakura

et al. 2015

Experimental Cell Research

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“…We recently reported that cancer cells that recover from damages induced by hypoxia, acidosis and glucose deprivation show mitochondrial remodeling, increased aerobic glycolysis, and exhibit a high rate of ATP production [23]. In this study, we explore the role of H 2 S in the process of recovery of cancer cells from damage.…”

Section: Introductionmentioning

confidence: 95%

A H2S-Nampt Dependent Energetic Circuit Is Critical to Survival and Cytoprotection from Damage in Cancer Cells

Sanokawa-Akakura

Ostrakhovitch²,

Akakura³

et al. 2014

PLoS ONE

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We recently demonstrated that cancer cells that recover from damage exhibit increased aerobic glycolysis, however, the molecular mechanism by which cancer cells survive the damage and show increased aerobic glycolysis remains unknown. Here, we demonstrate that diverse cancer cells that survive hypoxic or oxidative damage show rapid cell proliferation, and develop tolerance to damage associated with increased production of hydrogen sulfide (H2S) which drives up-regulation of nicotinamide phosphoribosyltransferase (Nampt). Consistent with existence of a H2S-Nampt energetic circuit, in damage recovered cancer cells, H2S, Nampt and ATP production exhibit a significant correlation. Moreover, the treatment of cancer cells with H2S donor, NaHS, coordinately increases Nampt and ATP levels, and protects cells from drug induced damage. Inhibition of cystathionine beta synthase (CBS) or cystathionase (CTH), enzymes which drive generation of H2S, decreases Nampt production while suppression of Nampt pathway by FK866, decreases H2S and ATP levels. Damage recovered cells isolated from tumors grown subcutaneously in athymic mice also show increased production of H2S, Nampt and ATP levels, associated with increased glycolysis and rapid proliferation. Together, these data show that upon recovery from potential lethal damage, H2S-Nampt directs energy expenditure and aerobic glycolysis in cancer cells, leads to their exponential growth, and causes a high degree of tolerance to damage. Identification of H2S-Nampt as a pathway responsible for induction of damage tolerance in cancer cells may underlie resistance to therapy and offers the opportunity to target this pathway as a means in treatment of cancer.

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“…In cancer cells, energy is generated by the aerobic glycolysis process rather than the mitochondria oxidative phosphorylation process. 11,12 Aerobic glycolysis of cancer cell proceeds in normoxic conditions, which is distinguished from the anaerobic glycolysis of normal cell. According to such phenomenon called "Warburg effect", cancer cells uptake glucose rapidly, generate the adenosine 5-triphosphate (ATP) by inefficient way, and produce lots of lactates that made the extracellular environment acidic.…”

Section: Introductionmentioning

confidence: 99%

Comparison of Metabolic Profiles of Normal and Cancer Cells in Response to Cytotoxic Agents

Kang¹,

Park²

2017

Journal of the Korean Magnetic Resonance Society

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Together with radiotherapy, chemotherapy using cytotoxic agents is one of the most common therapies in cancer. Metabolic changes in cancer cells are drawing much attention recently, but the metabolic alterations by anticancer agents have not been much studied. Here, we investigated the effects of commonly used cytotoxic agents on lung normal cell MRC5 and lung cancer cell A549. We employed cis-plastin, doxorubicin, and 5-Fluorouracil and compared their effects on the viability and metabolism of the normal and cancer cell lines. We first established the concentration of the cytotoxic reagents that give differences in the viabilities of normal and cancer cell lines. In those conditions, the viability of A549 decreased significantly, whereas that of MRC5 remained unchanged. To study the metabolic alterations implicated in the viability differences, we obtained the metabolic profiles using 1 H-NMR spectrometry. The 1 H-NMR data showed that the metabolic changes of A549 cells are more remarkable than that of MRC5 cells and the effect of 5-FU on the A549 cells is the most distinct compared to other treatments. Heat map analysis showed that metabolic alterations under treatment of cytotoxic agents are totally different between normal and cancer cells. Multivariate analysis and weighted correlation network analysis (WGCNA) revealed a distinctive metabolite signature and hub metabolites. Two different analysis tools revealed that the changes of cell metabolism in response to cytotoxic agents were highly correlated with the Warburg effect and Reductive lipogenesis, two pathways having important effects on the cell survival. Taken together, our study addressed the correlation between the viability and metabolic profiles of MRC5 and A549 cells upon the treatment of cytotoxic anticancer agents.

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Cancer cells recovering from damage exhibit mitochondrial restructuring and increased aerobic glycolysis

Cited by 9 publications

References 22 publications

Dedifferentiation of cancer cells following recovery from a potentially lethal damage is mediated by H2S–Nampt

Dedifferentiation of cancer cells following recovery from a potentially lethal damage is mediated by H2S–Nampt

A H2S-Nampt Dependent Energetic Circuit Is Critical to Survival and Cytoprotection from Damage in Cancer Cells

Comparison of Metabolic Profiles of Normal and Cancer Cells in Response to Cytotoxic Agents

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