Double genetic disruption of lactate dehydrogenases A and B is required to ablate the “Warburg effect” restricting tumor growth to oxidative metabolism

Journal of Biological Chemistry, Journal Year: 2018, Volume and Issue: 293(41), P. 15947 - 15961

Published: Aug. 29, 2018

Language: Английский

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Genetic Ablation of the Cystine Transporter xCT in PDAC Cells Inhibits mTORC1, Growth, Survival, and Tumor Formation via Nutrient and Oxidative Stresses

Cancer Research, Journal Year: 2019, Volume and Issue: 79(15), P. 3877 - 3890

Published: June 7, 2019

Although chemoresistance remains a primary challenge in the treatment of pancreatic ductal adenocarcinoma (PDAC), exploiting oxidative stress might offer novel therapeutic clues. Here we explored potential targeting cystine/glutamate exchanger (SLC7A11/xCT), which contributes to maintenance intracellular glutathione (GSH). Genomic disruption xCT via CRISPR-Cas9 was achieved two PDAC cell lines, MiaPaCa-2 and Capan-2, xCT-KO clones were cultivated presence N-acetylcysteine. several cystine/cysteine transporters have been identified, our findings demonstrate that, vitro, plays major role cysteine balance GSH biosynthesis. As consequence, both lines exhibited amino acid with activation GCN2 subsequent induction ATF4, inhibition mTORC1, proliferation arrest, death. Tumor xenograft growth delayed but not suppressed cells, indicated key also additional mechanisms for homeostasis vivo. Moreover, rapid depletion cells led accumulation lipid peroxides swelling. These hallmarks ferroptotic death prevented by vitamin E or iron chelation. Finally, vitro pharmacologic low concentrations erastin phenocopied potentiated cytotoxic effects gemcitabine cisplatin lines. In conclusion, strongly support that xCT, its dual nutritional cellular stresses, has great as an anticancer strategy. SIGNIFICANCE: The is essential redox therapy inducing ferroptosis.

Language: Английский

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Altered gut metabolites and microbiota interactions are implicated in colorectal carcinogenesis and can be non-invasive diagnostic biomarkers

Microbiome, Journal Year: 2022, Volume and Issue: 10(1)

Published: Feb. 21, 2022

Abstract Background Gut microbiota contributes to colorectal cancer (CRC) pathogenesis through microbes and their metabolites. The importance of microbiota-associated metabolites in carcinogenesis highlights the need investigate gut metabolome along adenoma-carcinoma sequence determine mechanistic implications CRC. To date, how which interactively promote early events CRC development are still largely unclear. We aim linkage carcinogenesis. Results performed metabolomics metagenomics profiling on fecal samples from 386 subjects including 118 patients, 140 adenomas (CRA) patients 128 healthy as normal controls (NC). identified differences metabolite profiles among NC, CRA groups by partial least squares-discriminant principal component analyses. Among altered metabolites, norvaline myristic acid showed increasing trends CRA, CRC-associated were enriched branched-chain amino acids, aromatic acids aminoacyl-tRNA biosynthesis pathways. Moreover, marker signature (twenty metabolites) classified NC with an area under curve (AUC) 0.80, AUC 0.79. Integrative analyses demonstrated that relationships bacteria across stages; certain associations exhibited or decreasing strengths while some reversed negative positive vice versa. Combinations markers improved diagnostic performances; vs AUC: 0.94; 0.92; 0.86, indicating a potential for diagnosis neoplasia. Conclusions This study underscores early-driver stages tumorigenesis. Integrated microbiome analysis demonstrates association perturbed Fecal can be utilized, addition bacteria, non-invasive

Language: Английский

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P-Glycoprotein: One Mechanism, Many Tasks and the Consequences for Pharmacotherapy of Cancers

Frontiers in Oncology, Journal Year: 2020, Volume and Issue: 10

Published: Oct. 26, 2020

P-glycoprotein or multidrug resistance protein (MDR1) is an adenosine triphosphate (ATP) binding cassette transporter (ABCB1) best known for being obstacle to successful pharmacotherapy of cancers. It prevents cellular uptake a large number structurally and functionally diverse compounds, including the majority cancer therapeutics, in this way causes resistance. Systemic inhibition overcoming however failed clinical settings. As forward face outcome, we first suggest broaden view on function, by its role immunity, taking into account metabolic pathways that control expression. In second part review, discuss mechanism which able accomplishes different tasks, show quantitative analysis substrate transport yield set thumb rules allow predicting whether compound modulator, substrate, inhibitor, inducer P-glycoprotein. third part, example, these are tested with drugs (inhibiting nuclear factor-κB) has been previously repurposed therapy.

Language: Английский

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TGF-β signaling in the tumor metabolic microenvironment and targeted therapies

Journal of Hematology & Oncology, Journal Year: 2022, Volume and Issue: 15(1)

Published: Sept. 17, 2022

Abstract Transforming growth factor-β (TGF-β) signaling has a paradoxical role in cancer progression, and it acts as tumor suppressor the early stages but promoter late of cancer. Once cells are generated, TGF-β is responsible for orchestration immunosuppressive microenvironment (TME) supports growth, invasion, metastasis, recurrence, therapy resistance. These progressive behaviors driven by an “engine” metabolic reprogramming Recent studies have revealed that regulates driver (TMME). Intriguingly, ligands act “endocrine” cytokine influence host metabolism. Therefore, having insight into TMME instrumental acknowledging its wide range effects designing new treatment strategies. Herein, we try to illustrate concise definition based on published literature. Then, review elaborate contribution rewiring at cellular (intracellular), tissular (intercellular), organismal (cancer-host) levels. Furthermore, propose three potential applications targeting TGF-β-dependent mechanism reprogramming, paving way TGF-β-related antitumor from perspective

Language: Английский

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Oxidative Stress in Cancer Therapy: Friend or Enemy?

ChemBioChem, Journal Year: 2022, Volume and Issue: 23(10)

Published: Jan. 10, 2022

Excessive cellular oxidative stress is widely perceived as a key factor in pathophysiological conditions and cancer development. Healthy cells use several mechanisms to maintain intracellular levels of reactive oxygen species (ROS) overall redox homeostasis avoid damage DNA, proteins, lipids. Cancer cells, contrast, exhibit elevated ROS upregulated protective antioxidant pathways. Counterintuitively, such enhanced defence provide therapeutic opportunity for the development drugs with different anticancer action (MoA). In this review, role are described. The tumour-suppressive tumour-promotive functions discussed, these two strategies (increasing or decreasing fight cancer) compared. Clinically approved demonstrated MoAs highlighted followed by description examples metal-based drug candidates causing via novel MoAs.

Language: Английский

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The role of glutaminase in cancer

Histopathology, Journal Year: 2019, Volume and Issue: 76(4), P. 498 - 508

Published: Oct. 9, 2019

Increased glutamine metabolism (glutaminolysis) is a hallmark of cancer and recognised as key metabolic change in cells. Breast heterogeneous disease with different morphological molecular subtypes responses to therapy, breast cells are known rewire support survival proliferation. Glutaminase isoenzymes (GLS GLS2) enzymes for metabolism. Interestingly, GLS GLS2 have contrasting functions tumorigenesis. In this review, we explore the role glutaminase cancer, primarily focusing on address played by oncogenes tumour suppressor genes regulating glutaminase, discuss current therapeutic approaches targeting glutaminase.

Language: Английский

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Effects of the Usage of l-Cysteine (l-Cys) on Human Health

Molecules, Journal Year: 2018, Volume and Issue: 23(3), P. 575 - 575

Published: March 3, 2018

This review summarizes recent knowledge about the use of amino acid l-Cysteine (l-Cys) through diet, nutritional supplements or drugs with aim to improve human health treat certain diseases. Three databases (PubMed, Scopus, and Web Science) different keywords have been used create a database documents published between 1950 2017 in scientific journals English Spanish. A total 60,885 primary publications were ultimately selected compile accurate information l-Cys medicine therapies identify reported benefits on health. The number for these purposes has increased significantly during last two decades. increase seems be closely related rise nutraceutical industries personalized medicine. main evidence reporting usage is summarized. However, lack studies based clinical trials hampers consensus among authors. Thus, debate role effectiveness supplements/drugs containing still open.

Language: Английский

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Implications of Antioxidant Systems in Inflammatory Bowel Disease

BioMed Research International, Journal Year: 2018, Volume and Issue: 2018, P. 1 - 7

Published: Jan. 1, 2018

The global incidence of inflammatory bowel disease (IBD), a group chronic gastrointestinal disorders, has been rising. preponderance evidence demonstrates that oxidative stress (OS) performs critical function in the onset IBD and manner its development. purpose this review is to outline generation reactive oxygen species antioxidant defense mechanisms tract role played by OS marking development IBD. Furthermore, various ways through which related genetic susceptibility mucosal immune response. experimental results suggest certain therapeutic regimens for could have favorable impact scavenging free radicals, reducing cytokine prooxidative enzyme concentrations, improving antioxidative capabilities cells. However, activity characterized high level specificity may be fundamental clinical therapies relapsing patients. Therefore, additional research required clarify pathogenesis progression

Language: Английский

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Psychological Stress and Cellular Aging in Cancer: A Meta-Analysis

Oxidative Medicine and Cellular Longevity, Journal Year: 2019, Volume and Issue: 2019, P. 1 - 23

Published: Nov. 13, 2019

Background . Epidemiological evidence continues to accumulate on the effect of psychosocial and behavioral factors in relation cancer risk, progression, mortality. Material Methods This article presents current relationship between psychological stress risk cellular aging process. Ten databases were searched identify publications up September 2019. References from retrieved articles also reviewed. We included nine review papers 26 cohort or case-control studies based inclusion/exclusion criteria. Results previously published did not show consistent for association stress, while previous is stronger regarding role chronic growth metastasis aging. In seven observational studies, severe life events, anxiety, depression, insufficient social support perception, avoiding coping strategy significantly associated with breast risk. For other specific types cancer, 11 reported increased stressful two others found mortality a decline treatment adherence. Conclusions Recent epidemiological generally suggests may be considered play key Understanding molecular mechanisms interaction important management prevention. The stressors should when developing evaluating change practice.

Language: Английский

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