scholarly journals TAMI-38. CYSTEINE-PROMOTING COMPOUNDS INDUCE MITOCHONDRIAL TOXICITY IN GLIOBLASTOMA THROUGH ALTERED PYRUVATE AND SERINE METABOLISM

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii221-ii221
Author(s):  
Evan Noch ◽  
Laura Palma ◽  
Isaiah Yim ◽  
Bhavneet Binder ◽  
Elisa Benedetti ◽  
...  
Keyword(s):  
Amino Acid ◽  
Cell Growth ◽  
Growth Inhibition ◽  
Glucose Deprivation ◽  
Tumor Metabolism ◽  
Metabolic Phenotype ◽  
Low Grade ◽  
Mitochondrial Toxicity ◽  
Human Cancers ◽  
Pathway Gene

Abstract Glioblastoma (GBM) remains a poorly treatable disease with high mortality. Tumor metabolism in GBM is a critical mechanism responsible for accelerated growth because of upregulation of glucose, amino acid, and fatty acid utilization. However, little is known about the metabolic alterations that are specific to GBM and that are targetable with FDA-approved compounds. To investigate tumor metabolism signatures unique to GBM, we interrogated the TCGA and a cancer metabolite database for alterations in glucose and amino acid signatures in GBM relative to other human cancers and relative to low-grade glioma. From these analyses, we found that GBM exhibits the highest levels of cysteine and methionine pathway gene expression of 32 human cancers and that GBM exhibits high levels of cysteine-related metabolites compared to low-grade gliomas. To study the role of cysteine in GBM pathogenesis, we treated patient-derived GBM cells with a variety of FDA-approved cyst(e)ine-promoting compounds in vitro, including N-acetylcysteine (NAC) and the cephalosporin antibiotic, Ceftriaxone (CTX), which induces cystine import through System Xc transporter upregulation. Cysteine-promoting compounds, including NAC and CTX, inhibit growth of GBM cells, which is exacerbated by glucose deprivation. This growth inhibition is associated with reduced mitochondrial metabolism, manifest by reduction in ATP, NADPH/NADP+ ratio, mitochondrial membrane potential, and oxygen consumption rate. Metabolic tracing experiments with 13C6-glucose demonstrate that L-serine is rapidly depleted in GBM cells upon treatment with NAC and CTX, and exogenous serine rescues NAC- and CTX-mediated cell growth inhibition. In addition, these compounds reduce GBM mitochondrial pyruvate transport. We show that cysteine-promoting compounds reduce cell growth and induce mitochondrial toxicity in GBM, which may be due to rapid serine depletion and reduced mitochondrial pyruvate transport. This metabolic phenotype is exacerbated by glucose deprivation. This pathway is targetable with FDA-approved cysteine-promoting compounds and could synergize with glucose-lowering treatments, including the ketogenic diet, for GBM.

P13.07 Cysteine induces glioblastoma cytotoxicity through mitochondrial reductive stress

2021 ◽  
Vol 23 (Supplement_2) ◽  
pp. ii33-ii34
Author(s):  
E Noch ◽  
L Palma ◽  
I Yim ◽  
D Barnett ◽  
B BHinder ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
Amino Acid ◽  
Glutathione Reductase ◽  
Glucose Deprivation ◽  
Mitochondrial Metabolism ◽  
Low Grade ◽  
Mitochondrial Toxicity ◽  
Reductive Stress ◽  
Human Cancers ◽  
Metabolite Database

Abstract BACKGROUND Glioblastoma (GBM) remains a poorly treatable disease with high mortality. Tumor metabolism in GBM is a critical mechanism responsible for accelerated growth because of upregulation of glucose, amino acid, and fatty acid utilization. However, therapies targeting GBM metabolism, whether through the use of small-molecule compounds or dietary interventions to limit nutrient sources, have failed in clinical trials. Metabolic bypass is an important mechanism that is often overlooked in GBM trials, since many trials have focused instead on combining anti-metabolic therapy with cytotoxic treatments. The goal of this research is to use a multi-pronged treatment approach with targeted drug and dietary therapy to leverage metabolic susceptibilities in GBM. MATERIALS AND METHODS We first interrogated the TCGA database and a cancer metabolite database for alterations in glucose and amino acid signatures in GBM relative to other human cancers and relative to low-grade glioma. We identified the amino acid cysteine as contributing to a novel metabolic susceptibility pathway in GBM. To study the role of cysteine in GBM pathogenesis, we treated patient-derived GBM cells with a variety of FDA-approved cysteine-promoting compounds in vitro, including N-acetylcysteine (NAC). We measured cell proliferation, energy production, mitochondrial metabolism, and reactive oxygen species to study mechanisms of oxidoreductive stress. Results: From our TCGA and cancer metabolite database analyses, we found that GBM exhibits the highest levels of cysteine and methionine pathway gene expression of 32 human cancers and that GBM exhibits high levels of cysteine-related metabolites compared to low-grade gliomas. Cysteine compounds, including NAC, reduce growth of GBM cells, which is exacerbated by glucose deprivation. This growth inhibition is associated with reduced mitochondrial metabolism, manifest by reduction in ATP generation, NADPH/NADP+ ratio, mitochondrial membrane potential, and oxygen consumption rate. Through measurement of mitochondrial hydrogen peroxide, we found that NAC-treated cells exhibit a paradoxical increase in mitochondrial hydrogen peroxide levels, likely due to inhibition of thioreductase and glutathione reductase systems. Through genetic and pharmacological studies, we found that induction of thioredoxin-2 rescues NAC-mediated cytotoxicity and that inhibition of thioreductase and glutathione reductase exacerbates mitochondrial toxicity and reductive stress. CONCLUSIONS We show that cysteine compounds reduce cell growth and induce mitochondrial toxicity in GBM through reductive stress. This metabolic phenotype is exacerbated by glucose deprivation. This pathway is targetable with FDA-approved cysteine-promoting compounds and could synergize with glucose-lowering treatments, including the ketogenic diet, for GBM.

scholarly journals FSMP-10. CYSTEINE INDUCES CYTOTOXICITY IN GLIOBLASTOMA THROUGH MITOCHONDRIAL HYDROGEN PEROXIDE PRODUCTION

2020 ◽  
Vol 3 (Supplement_1) ◽  
pp. i18-i18
Author(s):  
Evan Noch ◽  
Laura Palma ◽  
Isaiah Yim ◽  
Bhavneet Binder ◽  
Elisa Benedetti ◽  
...  
Keyword(s):  
Amino Acid ◽  
Treated Patient ◽  
Glucose Deprivation ◽  
H2o2 Production ◽  
Low Grade ◽  
Reductive Stress ◽  
Human Cancers ◽  
Pathway Gene ◽  
O2 Reduction

Abstract Glioblastoma (GBM) is a poorly treatable disease with high mortality. Tumor metabolism in GBM is a critical mechanism responsible for growth because of upregulation of glucose, amino acid, and fatty acid utilization. However, little is known about the specific metabolic alterations in GBM that are targetable with FDA-approved compounds. To investigate metabolic signatures unique to GBM, we interrogated the TCGA and a cancer metabolite database for alterations in glucose and amino acid signatures in GBM relative to other human cancers and relative to low-grade glioma. From these analyses, we found that GBM exhibits the highest levels of cysteine and methionine pathway gene expression of 32 human cancers and that GBM exhibits high levels of cysteine metabolites compared to low-grade gliomas. To study the role of cysteine in GBM pathogenesis, we treated patient-derived GBM cells with FDA-approved cyst(e)ine-promoting compounds in vitro, including N-acetylcysteine (NAC) and the cephalosporin antibiotic, Ceftriaxone (CTX), which induces cystine import through system Xc transporter upregulation. Cysteine-promoting compounds, including NAC and CTX, inhibit growth of GBM cells, which is exacerbated by glucose deprivation. This growth inhibition is associated with reduced mitochondrial metabolism, manifest by reduction in ATP, NADPH/NADP+ ratio, mitochondrial membrane potential, and oxygen consumption rate. Mechanistic experiments revealed that cysteine compounds induce a rapid increase in the rate of H2O2 production in isolated GBM mitochondria, an effect blocked by the H2O2 scavenger, catalase. Such findings are consistent with reductive stress, a ROS-producing process whereby excess mitochondrial reducing equivalents prevent electron transfer to oxidized electron acceptors, inducing O2 reduction to H2O2. We show that cysteine-promoting compounds reduce cell growth and induce rapid mitochondrial toxicity in GBM, which may be due to reductive stress. This pathway is targetable with FDA-approved cysteine-promoting compounds and could synergize with glucose-lowering treatments, including the ketogenic diet, for GBM.

Amino acid uptake regulation by cell growth in cultured hepatocytes isolated from fetal and adult rats

1992 ◽  
Vol 12 (2) ◽  
pp. 135-141 ◽  
Author(s):  
S. Leoni ◽  
S. Spagnuolo ◽  
M. Massimi ◽  
F. Terenzi ◽  
L. Conti Devirgiliis
Keyword(s):  
Amino Acid ◽  
Cell Growth ◽  
Growth Inhibition ◽  
Cell Density ◽  
Amino Acid Uptake ◽  
Growth Stimulation ◽  
Acid Uptake ◽  
Adult Rats ◽  
Dependent Growth ◽  
Differentiation Stage

Amino acid uptake mediated by system A was studied in cultured fetal and adult hepatocytes, subjected to growth stimulation by EGF and insulin, or to growth inhibition by high cell density. The mitogenic stimulation induced a strong transport increase only in fetal cells, while the cell density-dependent growth inhibition, probably mediated by molecules present on adult hepatocyte membranes, provoked the decrease of amino acid uptake only in the adult cells. The results indicate that the different modulation of amino acid transport by cell growth is dependent on the age and the differentiation stage of hepatocytes.

scholarly journals Anti-Tumour Effects of High Affinity L-type Amino Acid Transporter1 Inhibitors on Human Pancreatic Adencarcinoma Cells

2017 ◽  
Vol 2 (2) ◽  
pp. 55-68
Author(s):  
Rafiqul Islam ◽  
Nesar Ahmed ◽  
Shamima Akhter Ferdousy ◽  
Mohammad Shah Jahirul Haque Chowdhury ◽  
Md Tauhidul Islam Chowdhury ◽  
...  
Keyword(s):  
Amino Acid ◽  
Cell Growth ◽  
Tumor Cell ◽  
Growth Inhibition ◽  
Life Span ◽  
Pancreatic Adenocarcinoma ◽  
Nude Mice ◽  
Dependent Manner ◽  
Tumor Cell Growth ◽  
Mib 1

Background: a system L transporter L-type amino acid transporter 1 (LAT1) is upregulated to support tumor cell growth in malignant tumor. Objective: The purpose of the present study was to investigate the growth inhibition and [14C] L-leucine transport in human pancreatic adenocarcinoma cells MAIPaCa-2 and BXPC3. Methodology: This animal study was carried out in Japan. The in vitro growth inhibition study was performed by using KYT0351 and KYT0353 which inhibited the tumor cell growth in dose dependent manner and uptake of [14C] L-leucine by MIAPaCa-2 and BXPC3 cells was Na+- independent and was strongly inhibited by KYT0351 and KYT0353. The in vivo tumor growth inhibition was also carried out by intra tumor injection of KYT0351 and KYT0353 at the concentration of 2.6mM of each on both the MIAPaCa-2 and BXPC3 nude mice tumor. Result: In a subsequent survival study with the intra peritoneal injection of ascites mice model, control mice had a mean life span of 20 ± 4.30 days and 21 ± 5 days in MIAPaCa-2 and BXPC3 cells respectively, whereas the intraperitoneal injection of 10mg/kg twice daily of KYT0351 and KYT0353 group had improved survival (mean life span 28.4 ± 8.5 and 34.4 ± 9.86 days, 26 ±4.52 and 31.8 ± 7.62 days respectively in MIAPaCa-2 and BXPC3 cells). Kaplan-Meier survival data of nude mice treated with KYT0351 and KYT0353 were significant. To study the mechanism of growth inhibition we investigated the MIB-1 proliferation assay and TUNEL assay. Significantly less MIB-1 staining and more apoptotic nuclei was detected in tumors treated with KYT0351 and KYT0353 in both MIAPaCa-2 and BXPC3 cells compared with saline treated group. Conclusion: In conclusion both the KYT0351 and KYT0353 is a potent LAT1-specific inhibitor and LAT1 could be one of the molecular target in pancreatic adenocarcinoma therapy. Journal of National Institute of Neurosciences Bangladesh, 2016;2(2): 55-68

scholarly journals Cysteine induces mitochondrial reductive stress in glioblastoma through hydrogen peroxide production

2021 ◽  
Author(s):  
Evan K Noch ◽  
Laura Palma ◽  
Isaiah Yim ◽  
Daniel Barnett ◽  
Alexander Walsh ◽  
...  
Keyword(s):  
Amino Acid ◽  
The Cancer Genome Atlas ◽  
Glucose Starvation ◽  
Mitochondrial Oxygen Consumption ◽  
Glucose Lowering ◽  
Reductive Stress ◽  
Human Cancers ◽  
Pathway Gene ◽  
Cancer Genome Atlas ◽  
Methionine Pathway

SummaryGlucose and amino acid metabolism are critical for glioblastoma (GBM) growth, but little is known about the specific metabolic alterations in GBM that are targetable with FDA-approved compounds. To investigate tumor metabolism signatures unique to GBM, we interrogated The Cancer Genome Atlas for alterations in glucose and amino acid signatures in GBM relative to other human cancers and found that GBM exhibits the highest levels of cysteine and methionine pathway gene expression of 32 human cancers. Treatment of patient-derived GBM cells with the FDA-approved cysteine compound N-acetylcysteine (NAC) reduce GBM cell growth and mitochondrial oxygen consumption, which was worsened by glucose starvation. Mechanistic experiments revealed that cysteine compounds induce rapid mitochondrial H2O2 production and reductive stress in GBM cells, an effect blocked by oxidized glutathione, thioredoxin, and redox enzyme overexpression. These findings indicate that GBM is uniquely susceptible to NAC-driven reductive stress and could synergize with glucose-lowering treatments for GBM.

Oncogenic LncRNA CASC9 in Cancer Progression

2020 ◽  
Vol 26 ◽  
Author(s):  
Yuying Qi ◽  
Chaoying Song ◽  
Jiali Zhang ◽  
Chong Guo ◽  
Chengfu Yuan
Keyword(s):  
Cell Proliferation ◽  
Drug Resistance ◽  
Cell Growth ◽  
Cancer Cells ◽  
Therapeutic Potential ◽  
Squamous Metaplasia ◽  
Neoplastic Transformation ◽  
Over Expression ◽  
Human Cancers ◽  
Current Review

Background: Long non-coding RNA (LncRNAs), with the length over 200 nucleotides, originate from intergenic, antisense, or promoter-proximal regions, is a large family of RNAs that lack coding capacity. Emerging evidences illustrated that LncRNAs played significant roles in a variety of cellular functions and biological processes in profuse human diseases, especially in cancers. Cancer susceptibility candidate 9 (CASC9), as a member of the LncRNAs group, was firstly found its oncogenic function in esophageal cancer. In following recent studies, a growing amount of human malignancies are verified to be correlated with CASC9, most of which are derived from the squamous epithelium tissue. This present review attempts to highlight the latest insights into the expression, functional roles, and molecular mechanisms of CASC9 in different human malignancies. Methods: In this review, the latest findings related to the pathophysiological processes of CASC9 in human cancers were summarized and analyzed, the associated studies were collected in systematically retrieval of PubMed used lncRNA and CASA9 as keywords. Results: CASC9 expression is identified to be aberrantly elevated in a variety of malignancies. The over-expression of CASC9 has been suggested to accelerate cell proliferation, migration, cell growth and drug resistance of cancer cells, while depress cell apoptosis, revealing its role as an oncogene. Moreover, the current review demonstrated CASC9 closely relates to neoplastic transformation of squamous epithelial cells and squamous metaplasia in non-squamous epithelial tissues. Finally, we discuss the limitations and tremendous diagnostic/therapeutic potential of CASC9 in various human cancers. Results: CASC9 expression is identified to be aberrantly elevated in a variety of malignancies. The over-expression of CASC9 has been suggested to accelerate cell proliferation, migration, cell growth and drug resistance of cancer cells, while depress cell apoptosis, revealing its role as an oncogene. Moreover, the current review demonstrated CASC9 closely relates to neoplastic transformation of squamous epithelial cells and squamous metaplasia in non-squamous epithelial tissues. Finally, we discuss the limitations and tremendous diagnostic/therapeutic potential of CASC9 in various human cancers. Conclusion: Long non-coding RNACASC9 likely served as useful disease biomarkers or therapy targets that could effectively apply in treatment of different kinds of cancers.

Jab1-siRNA Induces Cell Growth Inhibition and Cell Cycle Arrest in Gall Bladder Cancer Cells via Targeting Jab1 Signalosome

2020 ◽  
Vol 19 (16) ◽  
pp. 2019-2033 ◽  
Author(s):  
Pratibha Pandey ◽  
Mohammad H. Siddiqui ◽  
Anu Behari ◽  
Vinay K. Kapoor ◽  
Kumudesh Mishra ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Bladder Cancer ◽  
Cell Growth ◽  
Gall Bladder ◽  
Growth Inhibition ◽  
Cell Cycle Arrest ◽  
Gall Bladder Cancer ◽  
Cell Growth Inhibition ◽  
Cycle Arrest ◽  
Apoptotic Induction

Background: The aberrant alteration in Jab1 signalosome (COP9 Signalosome Complex Subunit 5) has been proven to be associated with the progression of several carcinomas. However the specific role and mechanism of action of Jab1 signalosome in carcinogenesis of gall bladder cancer (GBC) are poorly understood. Objective: The main objective of our study was to elucidate the role and mechanism of Jab1 signalosome in gall bladder cancer by employing siRNA. Methods: Jab1 overexpression was identified in gall bladder cancer tissue sample. The role of Jab1-siRNA approach in cell growth inhibition and apoptotic induction was then examined by RT-PCR, Western Blotting, MTT, ROS, Hoechst and FITC/Annexin-V staining. Results: In the current study, we have shown that overexpression of Jab1 stimulated the proliferation of GBC cells; whereas downregulation of Jab1 by using Jab1-siRNA approach resulted incell growth inhibition and apoptotic induction. Furthermore, we found that downregulation of Jab1 induces cell cycle arrest at G1 phase and upregulated the expression of p27, p53 and Bax gene. Moreover, Jab1-siRNA induces apoptosis by enhancing ROS generation and caspase-3 activation. In addition, combined treatment with Jab1-siRNA and gemicitabine demonstrated an enhanced decline in cell proliferation which further suggested increased efficacy of gemcitabine at a very lower dose (5μM) in combination with Jab1-siRNA. Conclusion: In conclusion, our study strongly suggests that targeting Jab1 signalosome could be a promising therapeutic target for the treatment of gall bladder cancer.

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