scholarly journals C/EBPβ-LIP dually activates glycolysis and the malate aspartate shuttle to maintain NADH/NAD+ homeostasis

2020 ◽  
Author(s):  
Tobias Ackermann ◽  
Hidde R. Zuidhof ◽  
Gertrud Kortman ◽  
Martijn G. S. Rutten ◽  
Mathilde Broekhuis ◽  
...  
Keyword(s):  
Cell Survival ◽  
Cancer Cell ◽  
De Novo ◽  
Atp Production ◽  
Transport Chain ◽  
Cancer Cell Survival ◽  
Inhibition Of Glycolysis ◽  
Factor C ◽  
Cell Growth And Proliferation ◽  
Malate Aspartate Shuttle

AbstractOncogene-induced metabolic reprograming supports cell growth and proliferation. Yet, it also links cancer cell survival to certain metabolic pathways and nutrients. In order to synthesise amino acids and nucleotides de novo for growth and proliferation, cancer cells depend on glycolysis, the cytoplasmic oxidation of glucose, which generates necessary metabolic intermediates and ATP. During glycolysis, NAD+ is used as the oxidizing agent and is thereby reduced into NADH. To ensure high glycolysis rates and maintain NADH/NAD+ homeostasis, cytoplasmic NAD+ has to be regenerated. The mitochondria are the major sites of NADH reoxidation into NAD+ where NADH-derived electrons enter the electron transport chain for ATP production. Since NADH/NAD+ cannot cross membranes, the malate-aspartate shuttle (MAS) or the glycerol-3-phosphate shuttle (GPS) are used as intermediate electron carriers. In addition, cytoplasmic NAD+ is generated by NADH-electron transfer to pyruvate, reducing it to lactate (the Warburg effect). NADH/NAD+ homeostasis plays a pivotal role in cancer cell survival, but our knowledge about the involved regulatory mechanisms is still limited. Here, we show that the proto-oncogenic transcription factor C/EBPβ-LIP stimulates both glycolysis and the MAS. Inhibition of glycolysis with ongoing C/EBPβ-LIP-induced MAS activity results in NADH depletion and apoptosis that can be rescued by inhibiting either the MAS or other NADH-consuming processes. Therefore, beyond the discovery of C/EBPβ-LIP as a dual activator of glycolysis and the MAS, this study indicates that simultaneous inhibition of glycolysis and lowering of the NADH/NAD+ ratio may be considered to treat cancer.

Co-targeting EGFR and Autophagy Impairs Ovarian Cancer Cell Survival during Detachment from the ECM

2015 ◽  
Vol 15 (3) ◽  
pp. 215-226 ◽  
Author(s):  
Zongyuan Yang ◽  
Yi Liu ◽  
Xiao Wei ◽  
Xiaoshui Zhou ◽  
Cheng Gong ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Survival ◽  
Cancer Cell ◽  
Ovarian Cancer Cell ◽  
Cancer Cell Survival

AMPA Receptor Antagonist CFM-2 Decreases Survivin Expression in Cancer Cells

2018 ◽  
Vol 18 (4) ◽  
pp. 591-596 ◽  
Author(s):  
Domingo Sanchez Ruiz ◽  
Hella Luksch ◽  
Marco Sifringer ◽  
Achim Temme ◽  
Christian Staufner ◽  
...  
Keyword(s):  
Cell Survival ◽  
Receptor Antagonist ◽  
Cancer Cells ◽  
Glutamate Receptors ◽  
Cancer Cell ◽  
Ampa Receptor ◽  
Ampa Receptors ◽  
Survivin Expression ◽  
Ampa Receptor Antagonist ◽  
Cancer Cell Survival

Background: Glutamate receptors are widely expressed in different types of cancer cells. α-Amino-3- hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors are ionotropic glutamate receptors which are coupled to intracellular signaling pathways that influence cancer cell survival, proliferation, and migration. Blockade of AMPA receptors by pharmacologic compounds may potentially constitute an effective tool in anticancer treatment strategies. Method: Here we investigated the impact of the AMPA receptor antagonist CFM-2 on the expression of the protein survivin, which is known to promote cancer cell survival and proliferation. We show that CFM-2 inhibits survivin expression at mRNA and protein levels and decreases the viability of cancer cells. Using a stably transfected cell line which overexpresses survivin, we demonstrate that over-expression of survivin enhances cancer cell viability and attenuates CFM-2–mediated inhibition of cancer cell growth. Result: These findings point towards suppression of survivin expression as a new mechanism contributing to anticancer effects of AMPA antagonists.

scholarly journals The ERG-Regulated LINC00920 Promotes Prostate Cancer Cell Survival via the 14-3-3ε–FOXO Pathway

2020 ◽  
Vol 18 (10) ◽  
pp. 1545-1559
Author(s):  
Arlou Kristina Angeles ◽  
Doreen Heckmann ◽  
Niclas Flosdorf ◽  
Stefan Duensing ◽  
Holger Sültmann
Keyword(s):  
Prostate Cancer ◽  
Cell Survival ◽  
Cancer Cell ◽  
Prostate Cancer Cell ◽  
Cancer Cell Survival

scholarly journals LONP1 and ClpP cooperatively regulate mitochondrial proteostasis for cancer cell survival

Oncogenesis ◽  
2021 ◽  
Vol 10 (2) ◽  
Author(s):  
Yu Geon Lee ◽  
Hui Won Kim ◽  
Yeji Nam ◽  
Kyeong Jin Shin ◽  
Yu Jin Lee ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Growth ◽  
Cell Survival ◽  
Cancer Cell ◽  
Stress Responses ◽  
Molecular Mechanisms ◽  
Tca Cycle ◽  
Mitochondrial Matrix ◽  
Mitochondrial Functions ◽  
Cancer Cell Survival

AbstractMitochondrial proteases are key components in mitochondrial stress responses that maintain proteostasis and mitochondrial integrity in harsh environmental conditions, which leads to the acquisition of aggressive phenotypes, including chemoresistance and metastasis. However, the molecular mechanisms and exact role of mitochondrial proteases in cancer remain largely unexplored. Here, we identified functional crosstalk between LONP1 and ClpP, which are two mitochondrial matrix proteases that cooperate to attenuate proteotoxic stress and protect mitochondrial functions for cancer cell survival. LONP1 and ClpP genes closely localized on chromosome 19 and were co-expressed at high levels in most human cancers. Depletion of both genes synergistically attenuated cancer cell growth and induced cell death due to impaired mitochondrial functions and increased oxidative stress. Using mitochondrial matrix proteomic analysis with an engineered peroxidase (APEX)-mediated proximity biotinylation method, we identified the specific target substrates of these proteases, which were crucial components of mitochondrial functions, including oxidative phosphorylation, the TCA cycle, and amino acid and lipid metabolism. Furthermore, we found that LONP1 and ClpP shared many substrates, including serine hydroxymethyltransferase 2 (SHMT2). Inhibition of both LONP1 and ClpP additively increased the amount of unfolded SHMT2 protein and enhanced sensitivity to SHMT2 inhibitor, resulting in significantly reduced cell growth and increased cell death under metabolic stress. Additionally, prostate cancer patients with higher LONP1 and ClpP expression exhibited poorer survival. These results suggest that interventions targeting the mitochondrial proteostasis network via LONP1 and ClpP could be potential therapeutic strategies for cancer.

Fr154 SMOKING INDUCES WEE1 EXPRESSION PROMOTING CANCER CELL SURVIVAL IN ESOPHAGEAL ADENOCARCINOMA

2021 ◽  
Vol 160 (6) ◽  
pp. S-240
Author(s):  
Zheng Chen ◽  
Heng Lu ◽  
Dunfa Peng ◽  
Wael El-Rifai
Keyword(s):  
Cell Survival ◽  
Esophageal Adenocarcinoma ◽  
Cancer Cell ◽  
Cancer Cell Survival

scholarly journals Osteoblast-Derived Paracrine and Juxtacrine Signals Protect Disseminated Breast Cancer Cells from Stress

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1366
Author(s):  
Russell Hughes ◽  
Xinyue Chen ◽  
Natasha Cowley ◽  
Penelope D. Ottewell ◽  
Rhoda J. Hawkins ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Survival ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Breast Cancer Cells ◽  
Metastatic Breast ◽  
Accessory Cell ◽  
Cancer Cell Survival

Metastatic breast cancer in bone is incurable and there is an urgent need to develop new therapeutic approaches to improve survival. Key to this is understanding the mechanisms governing cancer cell survival and growth in bone, which involves interplay between malignant and accessory cell types. Here, we performed a cellular and molecular comparison of the bone microenvironment in mouse models representing either metastatic indolence or growth, to identify mechanisms regulating cancer cell survival and fate. In vivo, we show that regardless of their fate, breast cancer cells in bone occupy niches rich in osteoblastic cells. As the number of osteoblasts in bone declines, so does the ability to sustain large numbers of breast cancer cells and support metastatic outgrowth. In vitro, osteoblasts protected breast cancer cells from death induced by cell stress and signaling via gap junctions was found to provide important juxtacrine protective mechanisms between osteoblasts and both MDA-MB-231 (TNBC) and MCF7 (ER+) breast cancer cells. Combined with mathematical modelling, these findings indicate that the fate of DTCs is not controlled through the association with specific vessel subtypes. Instead, numbers of osteoblasts dictate availability of protective niches which breast cancer cells can colonize prior to stimulation of metastatic outgrowth.

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