How the Warburg effect supports aggressiveness and drug resistance of cancer cells?

Icard, Philippe; Shulman, S.; Farhat, Diana; Steyaert, Jean-Marc; Alifano, Marco; Lincet, Hubert

doi:10.1016/j.drup.2018.03.001

Cited by 402 publications

(324 citation statements)

References 237 publications

Supporting

Mentioning

300

Contrasting

Order By: Relevance

“…methotrexate, pralatrexate, raltitrexed) interacting with the folate transporters SLC19A1/RFC1 (reduced folate carrier 1) and SLC46A1/PCFT (proton-coupled folate transporter) 15 , or the nucleoside transporter SLC29A1/ENT1 (equilibrative nucleoside transporter 1) interacting with several nucleoside analogs such as clofarabine, gemcitabine and fluorouracil 16 . In parallel, modulation of transporter activity or expression levels has been shown to affect the efficacy of drugs, independently from direct uptake events, through their effects on cellular metabolic processes such as glycolysis and oxidative phosphorylation [17][18][19] .…”

Section: Introductionmentioning

confidence: 99%

A widespread role for SLC transmembrane transporters in resistance to cytotoxic drugs

Gottardi

César-Razquin

Παπακώστας

et al. 2019

Preprint

View full text Add to dashboard Cite

The activity and potency of a drug is inherently affected by the metabolic state of its target cell.Solute Carriers (SLCs) represent the largest family of transmembrane transporters in humans and constitute major determinants of cellular metabolism. Several SLCs have been shown to be required for the uptake of individual chemical compounds into cellular systems, but systematic surveys of transporter-drug relationships in human cells are currently lacking. We performed a series of genetic screens in the haploid human cell line HAP1 using a set of 60 cytotoxic compounds representative of the chemical space populated by approved drugs. By using a SLC-focused CRISPR/Cas9 lentiviral library, we identified transporters whose absence induced resistance to the drugs tested. Among the hundreds of drug-SLC relationships identified, we confirmed the role of the folate transporter SLC19A1 on the activity of antifolates and of SLC29A1 on several nucleoside analogs. Among the newly discovered dependencies, we identified the transporters SLC11A2/SLC16A1 for artemisinin derivatives and SLC35A2/SLC38A5 for cisplatin. The functional dependence on SLCs observed for a significant proportion of the compounds screened suggested a widespread role for SLCs in the uptake and cellular activity of cytotoxic drugs and provided an experimentally validated set of SLC-drug associations for a number of clinically relevant compounds.

show abstract

Section: Introductionmentioning

confidence: 99%

A widespread role for SLC transmembrane transporters in resistance to cytotoxic drugs

Gottardi

César-Razquin

Παπακώστας

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…We think that the presented results may open the way for a novel framework of research with interesting implications for the study of cancer cells where increased glucose utilization and altered glycolytic flux occur independently to oxygen availability [27] [28]. In case of proinflammatory stimuli, for example, the induction of a metabolic switch leading to upregulation of aerobic glycolysis [29] lead to an enhanced utilization of glucose which sustains the high rate of cell proliferation and invasiveness [30]. The role of Gcn5 and Ubp8 affecting protein ubiquitylation in yeast is a novel finding shedding light on the importance of the epigenetic post-translational regulation not only for the regulation of nucleosomes accessibility but also at metabolic level for sugar utilization.…”

Section: Discussionmentioning

confidence: 81%

Gcn5 and Ubp8 dependent ubiquitylation affects glycolysis in yeast

Palma

Fanelli

Cretella

et al. 2019

Preprint

View full text Add to dashboard Cite

Many of the molecular mechanisms affected by ubiquitylation are highly conserved from yeast to humans and are associated to a plethora of diseases including cancers. To elucidate the regulatory role of epigenetic factors such as the catalytic subunits of SAGA complex, KAT-Gcn5 and Ub-protease Ubp8, on ubiquitylation of non-histone proteins we have performed a comprehensive analysis of the Ub-proteome in yeast Saccharomyces cerevisiae in strains disrupted in Gcn5, Ubp8 or both respect to wild type. We found significative alteration of ubiquitylation in proteins belonging to different functional categories novel regulatory pathway and, considering that lowering glycolysis is a promising strategy to target tumor metabolism, we propose this study as an interesting perspective to lower enhanced glycolysis in tumors.

show abstract

“…The Warburg effect was first recognized in metabolic remodeling: energy production in aerobic environments is primarily dependent on glycolysis in tumor cells. Metabolic reprogramming occurs not only during the transformation of normal cells into tumor cells, but also during the development of advanced tumor cells and the self-renewal of tumor stem cells, which is closely related to the sensitivity of anticancer drugs and tumor metastasis potential [3][4][5][6]. Multiple interactions between proto-oncogenes and tumor suppressor genes, including Hif-1, c-Myc, AMPK, and PI3K, co-mediate reprogramming of tumor metabolism.…”

Section: Introductionmentioning

confidence: 99%

ROS-triggered AMPK de-SUMOylation promotes Warburg effect in hepatocellular carcinoma cells

Zhang

2020

Preprint

View full text Add to dashboard Cite

Hepatocellular carcinoma (HCC) is the most common malignant tumor of the liver characterized by high recurrence rate and high mortality. The interaction of oxidative stress tolerance and glycometabolism reprogramming in cancer cells results in metastasis and drug resistance in HCC. AMP-activated protein kinase (AMPK) is the master switch of cellular energy metabolism, which regulates the expression of glycolytic rate-limiting enzymes at multiple levels. SUMO Specific Peptidases (SENPs) respond to oxidative stress and modulate AMPK activity. Key scientific issues of this project: Activation of SENP5 by reactive oxygen species (ROS) triggered AMPKα2 de-SUMOylation and cytoplasmic retention to promote the Warburg effect in HCC cells. The human HCC cell lines SMMC-7721 and HepG2 were used in this project. H2O2 (200μM) was used to simulates oxidative stress in HCC cells. Glycolysis flow was monitored by Seahorse XF Extracellular Flux Analyzers. Western blot and immunofluorescence were used to evaluate expression and localization of AMPKα2. Data from TCGA database validated the correlation between SENP5 and glycolysis limiting enzymes. Results: (1) ROS-activated SNEP5 promoted Warburg effect; (2) SENP5 inhibited SUMO2/3 modification and nuclear translocation of AMPKα2; (3) Nuclear localized AMPKα2 activated FOXO3 to inhibit the Warburg effect mediated by c-Myc/Hif-α; (4) ROS activated SENP5 induced sorafenib resistance and epithelial mesenchymal transformation in HCC cells. Conclusion: SENP5 modifies the activation and localization of AMPK to promote glycometabolism reprogramming in HCC. This project provides a new theoretical bases for the treatment of HCC. Peptidase 5; Warburg effect Graphic abstract ROS activation of SENP5 mediates AMPKα2 de-SUMOylation and cytoplasmic retention, which promotes Warburg effect of liver cancer cells

show abstract

How the Warburg effect supports aggressiveness and drug resistance of cancer cells?

Cited by 402 publications

References 237 publications

A widespread role for SLC transmembrane transporters in resistance to cytotoxic drugs

A widespread role for SLC transmembrane transporters in resistance to cytotoxic drugs

Gcn5 and Ubp8 dependent ubiquitylation affects glycolysis in yeast

ROS-triggered AMPK de-SUMOylation promotes Warburg effect in hepatocellular carcinoma cells

Contact Info

Product

Resources

About