scholarly journals Fer and FerT Govern Mitochondrial Susceptibility to Metformin and Hypoxic Stress in Colon and Lung Carcinoma Cells

Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 97
Author(s):  
Odeya Marciano ◽  
Linoy Mehazri ◽  
Sally Shpungin ◽  
Alexander Varvak ◽  
Eldad Zacksenhaus ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Aerobic Glycolysis ◽  
Metastatic Cancer ◽  
Carcinoma Cells ◽  
Metabolic Adaptation ◽  
Hypoxic Stress ◽  
Lung Carcinoma Cells ◽  
Metabolic Role ◽  
Highly Sensitive ◽  
Anticancer Treatment

Aerobic glycolysis is an important metabolic adaptation of cancer cells. However, there is growing evidence that reprogrammed mitochondria also play an important metabolic role in metastatic dissemination. Two constituents of the reprogrammed mitochondria of cancer cells are the intracellular tyrosine kinase Fer and its cancer- and sperm-specific variant, FerT. Here, we show that Fer and FerT control mitochondrial susceptibility to therapeutic and hypoxic stress in metastatic colon (SW620) and non-small cell lung cancer (NSCLC-H1299) cells. Fer- and FerT-deficient SW620 and H1299 cells (SW∆Fer/FerT and H∆Fer/FerT cells, respectively) become highly sensitive to metformin treatment and to hypoxia under glucose-restrictive conditions. Metformin impaired mitochondrial functioning that was accompanied by ATP deficiency and robust death in SW∆Fer/FerT and H∆Fer/FerT cells compared to the parental SW620 and H1299 cells. Notably, selective knockout of the fer gene without affecting FerT expression reduced sensitivity to metformin and hypoxia seen in SW∆Fer/FerT cells. Thus, Fer and FerT modulate the mitochondrial susceptibility of metastatic cancer cells to hypoxia and metformin. Targeting Fer/FerT may therefore provide a novel anticancer treatment by efficient, selective, and more versatile disruption of mitochondrial function in malignant cells.

scholarly journals A combined computational pipeline to detect circular RNAs in human cancer cells under hypoxic stress

2019 ◽  
Vol 11 (10) ◽  
pp. 829-844 ◽  
Author(s):  
Antonella Di Liddo ◽  
Camila de Oliveira Freitas Machado ◽  
Sandra Fischer ◽  
Stefanie Ebersberger ◽  
Andreas W Heumüller ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Human Cancer ◽  
Cancer Cell Lines ◽  
Metabolic Adaptation ◽  
Circular Rnas ◽  
Hypoxic Stress ◽  
Computational Pipeline ◽  
Transcriptional Responses

Abstract Hypoxia is associated with several diseases, including cancer. Cells that are deprived of adequate oxygen supply trigger transcriptional and post-transcriptional responses, which control cellular pathways such as angiogenesis, proliferation, and metabolic adaptation. Circular RNAs (circRNAs) are a novel class of mainly non-coding RNAs, which have been implicated in multiple cancers and attract increasing attention as potential biomarkers. Here, we characterize the circRNA signatures of three different cancer cell lines from cervical (HeLa), breast (MCF-7), and lung (A549) cancer under hypoxia. In order to reliably detect circRNAs, we integrate available tools with custom approaches for quantification and statistical analysis. Using this consolidated computational pipeline, we identify ~12000 circRNAs in the three cancer cell lines. Their molecular characteristics point to an involvement of complementary RNA sequences as well as trans-acting factors in circRNA biogenesis, such as the RNA-binding protein HNRNPC. Notably, we detect a number of circRNAs that are more abundant than their linear counterparts. In addition, 64 circRNAs significantly change in abundance upon hypoxia, in most cases in a cell type-specific manner. In summary, we present a comparative circRNA profiling in human cancer cell lines, which promises novel insights into the biogenesis and function of circRNAs under hypoxic stress.

scholarly journals Inhibition of Kv10.1 Channels Sensitizes Mitochondria of Cancer Cells to Antimetabolic Agents

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 920 ◽  
Author(s):  
Ileana Hernández-Reséndiz ◽  
David Pacheu-Grau ◽  
Araceli Sánchez ◽  
Luis A. Pardo
Keyword(s):  
Cancer Cells ◽  
Therapeutic Target ◽  
Mitochondrial Dynamics ◽  
Metastatic Cancer ◽  
Combined Therapy ◽  
Mitochondrial Metabolism ◽  
Metabolic Adaptation ◽  
Approaches To Study ◽  
Novel Strategy ◽  
The Impact

Reprogramming of energy metabolism constitutes one of the hallmarks of cancer and is, therefore, an emerging therapeutic target. We describe here that the potassium channel Kv10.1, which is frequently overexpressed in primary and metastatic cancer, and has been proposed a therapeutic target, participates in metabolic adaptation of cancer cells through regulation of mitochondrial dynamics. We used biochemical and cell biological techniques, live cell imaging and high-resolution microscopy, among other approaches, to study the impact of Kv10.1 on the regulation of mitochondrial stability. Inhibition of Kv10.1 expression or function led to mitochondrial fragmentation, increase in reactive oxygen species and increased autophagy. Cells with endogenous overexpression of Kv10.1 were also more sensitive to mitochondrial metabolism inhibitors than cells with low expression, indicating that they are more dependent on mitochondrial function. Consistently, a combined therapy using functional monoclonal antibodies for Kv10.1 and mitochondrial metabolism inhibitors resulted in enhanced efficacy of the inhibitors. Our data reveal a new mechanism regulated by Kv10.1 in cancer and a novel strategy to overcome drug resistance in cancers with a high expression of Kv10.1.

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

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.

scholarly journals From Toxicity to Selectivity: Coculture of the Fluorescent Tumor and Non-Tumor Lung Cells and High-Throughput Screening of Anticancer Compounds

2021 ◽  
Vol 12 ◽  
Author(s):  
D.A. Skvortsov ◽  
M.A. Kalinina ◽  
I.V. Zhirkina ◽  
L.A. Vasilyeva ◽  
Y.A. Ivanenkov ◽  
...  
Keyword(s):  
Cancer Cells ◽  
High Throughput ◽  
High Throughput Screening ◽  
Fluorescent Proteins ◽  
Carcinoma Cells ◽  
Anticancer Compounds ◽  
Fluorescent Cell ◽  
Lung Carcinoma Cells ◽  
Cancerous Cells ◽  
Independent Assay

For the search of anticancer compounds in modern large chemical libraries, new approaches are of great importance. Cocultivation of the cells of tumor and non-tumor etiology may reveal specific action of chemicals on cancer cells and also take into account some effects of the tumor cell’s microenvironment. The fluorescent cell cocultivation test (FCCT) has been developed for screening of substances that are selectively cytotoxic on cancerous cells. It is based on the mixed culture of lung carcinoma cells A549’_EGFP and noncancerous fibroblasts of lung VA13_Kat, expressing different fluorescent proteins. Analysis of the cells was performed with the high-resolution scanner to increase the detection rate. The combination of cocultivation of cells with scanning of fluorescence reduces the experimental protocol to three steps: cells seeding, addition of the substance, and signal detection. The FCCT analysis does not disturb the cells and is compatible with other cell-targeted assays. The suggested method has been adapted for a high-throughput format and applied for screening of 2,491 compounds. Three compounds were revealed to be reproducibly selective in the FCCT although they were invisible in cytotoxicity tests in individual lines. Six structurally diverse indole, coumarin, sulfonylthiazol, and rifampicin derivatives were found and confirmed with an independent assay (MTT) to be selectively cytotoxic to cancer cells in the studied model.

Ocimum sanctuminduces apoptosis in A549 lung cancer cells and suppresses thein vivogrowth of lewis lung carcinoma cells

2009 ◽  
Vol 23 (10) ◽  
pp. 1385-1391 ◽  
Author(s):  
Venkataraman Magesh ◽  
Jang-Choon Lee ◽  
Kwang Seok Ahn ◽  
Hyo-Jung Lee ◽  
Hyo-Jeong Lee ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Lung Carcinoma ◽  
Lewis Lung Carcinoma ◽  
Carcinoma Cells ◽  
Lung Cancer Cells ◽  
Lewis Lung ◽  
Lung Carcinoma Cells ◽  
Lewis Lung Carcinoma Cells ◽  
A549 Lung

scholarly journals Loss of Fer Jeopardizes Metabolic Plasticity and Mitochondrial Homeostasis in Lung and Breast Carcinoma Cells

2021 ◽  
Vol 22 (7) ◽  
pp. 3387
Author(s):  
Linoy Mehazri ◽  
Sally Shpungin ◽  
Shai Bel ◽  
Uri Nir
Keyword(s):  
Electron Transport ◽  
Cancer Cells ◽  
Electron Transport Chain ◽  
Metastatic Cancer ◽  
Carcinoma Cells ◽  
Metabolic System ◽  
Cycle Progression ◽  
Metabolic Plasticity ◽  
Transport Chain ◽  
Metabolic Systems

Metabolic plasticity is a hallmark of the ability of metastatic cancer cells to survive under stressful conditions. The intracellular Fer kinase is a selective constituent of the reprogramed mitochondria and metabolic system of cancer cells. In the current work, we deciphered the modulatory roles of Fer in the reprogrammed metabolic systems of metastatic, lung (H358), non-small cell lung cancer (NSCLC), and breast (MDA-MB-231), triple-negative breast cancer (TNBC), carcinoma cells. We show that H358 cells devoid of Fer (H358ΔFer), strictly depend on glucose for their proliferation and growth, and fail to compensate for glucose withdrawal by oxidizing and metabolizing glutamine. Furthermore, glucose deficiency caused increased reactive oxygen species (ROS) production and induction of a DNA damage response (DDR), accompanied by the onset of apoptosis and attenuated cell-cycle progression. Analysis of mitochondrial function revealed impaired respiratory and electron transport chain (ETC) complex 1 (comp. I) activity in the Fer-deficient H358ΔFer cells. This was manifested by decreased levels of NAD+ and ATP and relatively low abundance of tricarboxylic acid (TCA) cycle metabolites. Impaired electron transport chain comp. I activity and dependence on glucose were also confirmed in Fer-deficient, MDA-MB-231ΔFer cells. Although both H358ΔFer and MDA-MB-231ΔFer cells showed a decreased aspartate level, this seemed to be compensated by the predominance of pyrimidines synthesis over the urea cycle progression. Notably, absence of Fer significantly impeded the growth of H358ΔFer and MDA-MB-231ΔFer xenografts in mice provided with a carb-deficient, ketogenic diet. Thus, Fer plays a key role in the sustention of metabolic plasticity of malignant cells. In compliance with this notion, targeting Fer attenuates the progression of H358 and MDA-MB-231 tumors, an effect that is potentiated by a glucose-restrictive diet.

scholarly journals A redox-dependent mechanism for AMPK dysregulation interrupts metabolic adaptation of cancer under glucose deprivation

2021 ◽  
Author(s):  
Younghwan Lee ◽  
Yoko Itahana ◽  
Choon Chen Ong ◽  
Koji Itahana
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Cell Lines ◽  
Aerobic Glycolysis ◽  
Glucose Deprivation ◽  
Redox System ◽  
Metabolic Adaptation ◽  
Acid Oxidation ◽  
Cancer Type ◽  
Metabolic Switch

AbstractAccelerated aerobic glycolysis is a distinctive metabolic property of cancer cells that confers dependency on glucose for survival. However, the selective therapeutic targeting of this vulnerability has yielded mixed results owing to the different sensitivities of each cancer type to glucose removal and lack of insight into the underlying mechanisms of glucose deprivation-induced cell death.Here, we screened multiple cell lines to determine their sensitivities to glucose deprivation and found that the cell lines most sensitive to glucose deprivation failed to activate AMPK, a major regulator of metabolic adaptation, resulting in metabolic catastrophe.Notably, glucose deprivation-induced AMPK dysregulation and rapid cell death were observed only in cancer cell lines with high expression of cystine/glutamate antiporter xCT. While this phenomenon was prevented by pharmacological or genetic inhibition of xCT, overexpression of xCT sensitized resistant cancer cells to glucose deprivation. We found that cystine uptake and glutamate export through xCT under glucose deprivation contributes to rapid NADPH depletion, leading to the collapse of the redox system, which subsequently inactivates AMPK by inhibitory oxidation and phosphorylation. This AMPK dysregulation caused a failure of metabolic switch to fatty acid oxidation upon glucose deprivation, resulting in mitochondrial dysfunction and cell death.Taken together, these findings suggest a novel cross-talk between the metabolic and signal transduction and reveal a metabolic vulnerability in xCT-high expressing cancer cells to glucose deprivation and provide a rationale for targeting glucose metabolism in these cancer cells.

scholarly journals A Kinome-Wide siRNA Screen Identifies Multiple Roles for Protein Kinases in Hypoxic Stress Adaptation, Including Roles for IRAK4 and GAK in Protection against Apoptosis in VHL−/− Renal Carcinoma Cells, Despite Activation of the NF-κB Pathway

2013 ◽  
Vol 18 (7) ◽  
pp. 782-796 ◽  
Author(s):  
Jing Pan ◽  
Jing Zhang ◽  
Andrew Hill ◽  
Peter Lapan ◽  
Steve Berasi ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Renal Carcinoma ◽  
Nuclear Factor Κb ◽  
Carcinoma Cells ◽  
Dominant Negative ◽  
Multiple Roles ◽  
Hypoxic Stress ◽  
Short Hairpin Rnas ◽  
Apoptotic Effects ◽  
Interfering Rna

Hypoxia induces changes to cancer cells that make them more resistant to treatment. We have looked at signaling pathways that facilitate these changes by screening the human kinome for effects on hypoxic responses in SW480 colon cancer cells. Hits identified in the screen were examined for effects on multiple molecular responses to hypoxia, including the endoplasmic reticulum stress and DNA damage responses in colon, melanoma, and renal cancer lines. To validate the hits from the small interfering RNA studies, we developed cell lines expressing stable short hairpin RNAs (shRNAs) in the A498 renal carcinoma cell line. Several lines, including those expressing shRNAs against DYRK1B, GAK, IHPK2, IRAK4, and MATK, showed an inability to form spheroid cultures. In addition, shRNAs targeting IRAK4 and GAK were incapable of 2D growth under anoxia. In the GAK shRNA-expressing line, nuclear factor–κB (NF-κB) was localized to the nucleus, but in the IRAK4 shRNA line, NF-κB levels were increased but the extent of nuclear localization was unchanged. Dominant negative mutants of IRAK4 and GAK also showed strong apoptotic effects in A498 cells under anoxia, supporting a direct link between these kinases and survival of the VHL−/− RCC line, which is typically highly resistant to hypoxic stress as a result of high and constitutive levels of Hif-1α.

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