ROS/PI3K/Akt and Wnt/β-catenin signalings activate HIF-1α-induced metabolic reprogramming to impart 5-fluorouracil resistance in colorectal cancer

Journal of Experimental & Clinical Cancer Research, Journal Year: 2022, Volume and Issue: 41(1)

Published: Jan. 8, 2022

Abstract Background Acquired resistance of 5-fluorouracil (5-FU) remains a clinical challenge in colorectal cancer (CRC), and efforts to develop targeted agents reduce have not yielded success. Metabolic reprogramming is key hallmark confers several tumor phenotypes including chemoresistance. Glucose metabolic events 5-FU CRC has been evaluated, whether abnormal glucose metabolism could impart also poorly defined. Methods Three separate acquired cell line models were generated, was assessed by measuring lactate utilization, RNA protein expressions metabolism-related enzymes changes intermediate metabolites metabolite pool. The levels hypoxia inducible factor 1α (HIF-1α) primary tumors circulating cells patients detected immunohistochemistry immunofluorescence. Stable HIF1A knockdown established with lentiviral system. influence both gene pharmacological inhibition on evaluated vivo vitro. Results abnormality 5-FU-resistant described detail. enhanced glycolysis pentose phosphate pathway associated increased HIF-1α expression. HIF-1α-induced imparted CRC. showed expression lines specimens, failure fluorouracil analog-based chemotherapy poor survival. Upregulation occurred through non-oxygen-dependent mechanisms reactive oxygen species-mediated activation PI3K/Akt signaling aberrant β-catenin the nucleus. Both knock-down restored sensitivity 5-FU. Conclusions potential biomarker for CRC, targeting HIF-1a combination may represent an effective therapeutic strategy

Language: Английский

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Taxanes in cancer treatment: Activity, chemoresistance and its overcoming

Drug Resistance Updates, Journal Year: 2021, Volume and Issue: 54, P. 100742 - 100742

Published: Jan. 1, 2021

Language: Английский

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Metformin: Is it a drug for all reasons and diseases?

Metabolism, Journal Year: 2022, Volume and Issue: 133, P. 155223 - 155223

Published: May 29, 2022

Metformin was first used to treat type 2 diabetes in the late 1950s and 2022 remains first-choice drug daily by approximately 150 million people. An accumulation of positive pre-clinical clinical data has stimulated interest re-purposing metformin a variety diseases including COVID-19. In polycystic ovary syndrome improves insulin sensitivity. 1 may help reduce dose. Meta-analysis from studies link reduction incidence cancer. Clinical trials, MILES (Metformin Longevity Study), TAME (Targeting Aging with Metformin), have been designed determine if can offset aging extend lifespan. Pre-clinical suggest that metformin, via suppression pro-inflammatory pathways, protection mitochondria vascular function, direct actions on neuronal stem cells, protect against neurodegenerative diseases. also studied for its anti-bacterial, -viral, -malaria efficacy. Collectively, these raise question: Is all diseases? It unclear as whether putative beneficial effects are secondary an anti-hyperglycemic insulin-sensitizing drug, or result other cellular actions, inhibition mTOR (mammalian target rapamycin), anti-viral actions. Clarification is sought ex vivo based use high concentrations be translated into benefits, they reflect 'Paracelsus' effect. The environmental impact no known metabolites, another emerging issue linked endocrine disruption fish, extensive T2D raised concerns over human reproduction. objectives this review to: 1) evaluate mechanism(s) action metformin; 2) analyze controversial evidence metformin's effectiveness treatment than diabetes; 3) assess reproducibility data, finally 4) reach informed conclusion reasons. We conclude primary benefits antihyperglycaemic secondarily contribute reduced risk number thereby enhancing healthspan. However, like improving endothelial function independent glucose homeostasis add therapeutic

Language: Английский

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The Metabolic Mechanisms of Breast Cancer Metastasis

Frontiers in Oncology, Journal Year: 2021, Volume and Issue: 10

Published: Jan. 7, 2021

Breast cancer is one of the most common malignancy among women worldwide. Metastasis mainly responsible for treatment failure and cause breast deaths. The role metabolism in progression metastasis gradually being emphasized. However, regulatory mechanisms that conduce to by metabolic reprogramming have not been expounded. cells exhibit different phenotypes depending on their molecular subtypes metastatic sites. Both intrinsic factors, such as MYC amplification, PIK3CA , TP53 mutations, extrinsic hypoxia, oxidative stress, acidosis, contribute cancers. Understanding underlying will provide important clues develop novel therapeutic approaches cancer.

Language: Английский

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The long and short non-coding RNAs modulating EZH2 signaling in cancer

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

Published: March 2, 2022

Non-coding RNAs (ncRNAs) are a large family of RNA molecules with no capability in encoding proteins. However, they participate developmental and biological processes their abnormal expression affects cancer progression. These can function as upstream mediators different signaling pathways enhancer zeste homolog 2 (EZH2) is among them. Briefly, EZH2 belongs to PRCs exert functional roles cells due its methyltransferase activity. gene via inducing H3K27me3. In the present review, our aim provide mechanistic discussion ncRNAs role regulating cancers. MiRNAs dually induce/inhibit affect downstream targets such Wnt, STAT3 EMT. Furthermore, miRNAs regulate therapy response affecting signaling. It noteworthy that reduce miRNA by binding promoter exerting Small-interfering (siRNA) short-hairpin (shRNA) synthetic, short capable reducing suppressing LncRNAs mainly targeting miRNAs. lncRNAs induce modulating expression. Circular (CircRNAs), like lncRNAs, areas discussed review focus on molecular leading clinical translation.

Language: Английский

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Doxorubicin and other anthracyclines in cancers: Activity, chemoresistance and its overcoming

Molecular Aspects of Medicine, Journal Year: 2023, Volume and Issue: 93, P. 101205 - 101205

Published: July 27, 2023

Anthracyclines have been important and effective treatments against a number of cancers since their discovery. However, use in therapy has complicated by severe side effects toxicity that occur during or after treatment, including cardiotoxicity. The mode action anthracyclines is complex, with several mechanisms proposed. It possible high due to the large set processes involved anthracycline action. development resistance major barrier successful treatment when using anthracyclines. This based on series studied addressed recent years. work provides an overview used cancer therapy. discusses activity, toxicity, chemoresistance, as well approaches improve decrease overcome resistance.

Language: Английский

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Unveiling the mechanisms and challenges of cancer drug resistance

Cell Communication and Signaling, Journal Year: 2024, Volume and Issue: 22(1)

Published: Feb. 12, 2024

Abstract Cancer treatment faces many hurdles and resistance is one among them. Anti-cancer strategies are evolving due to innate acquired capacity, governed by genetic, epigenetic, proteomic, metabolic, or microenvironmental cues that ultimately enable selected cancer cells survive progress under unfavorable conditions. Although the mechanism of drug being widely studied generate new target-based drugs with better potency than existing ones. However, broader flexibility in resistance, advanced therapeutic options efficacy need be explored. Combination therapy an alternative a success rate though risk amplified side effects commonplace. Moreover, recent groundbreaking precision immune ways overcome has revolutionized anticancer greater extent only limitation individual-specific needs further attention. This review will focus on challenges opted withstand current therapies at molecular level also highlights emerging -like immunological, stem cell-based may prove have potential challenge problem resistance.

Language: Английский

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The role of AMPK in cancer metabolism and its impact on the immunomodulation of the tumor microenvironment

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: Feb. 15, 2023

Adenosine monophosphate-activated protein kinase (AMPK) is a key metabolic sensor that pivotal for the maintenance of cellular energy homeostasis. AMPK contributes to diverse and physiological effects besides its fundamental role in glucose lipid metabolism. Aberrancy signaling one determining factors which lead development chronic diseases such as obesity, inflammation, diabetes, cancer. The activation downstream cascades orchestrate dynamic changes tumor bioenergetics. It well documented possesses suppressor context progression by modulating inflammatory pathways. In addition, plays central potentiating phenotypic functional reprogramming various classes immune cells reside microenvironment (TME). Furthermore, AMPK-mediated responses facilitate recruitment certain types TME, impedes development, progression, metastasis Thus, appears play an important regulation anti-tumor response regulating plasticity cells. effectuates modulation immunity via nutrient TME virtue molecular crosstalk with major checkpoints. Several studies including from our lab emphasize on anticancer several phytochemicals, are potential drug candidates. scope this review encompasses significance cancer metabolism influence drivers within special emphasis use phytochemicals target combat

Language: Английский

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METTL5 stabilizes c‐Myc by facilitating USP5 translation to reprogram glucose metabolism and promote hepatocellular carcinoma progression

Cancer Communications, Journal Year: 2023, Volume and Issue: 43(3), P. 338 - 364

Published: Jan. 5, 2023

Abstract Background Hepatocellular carcinoma (HCC) is one of the most prevalent cancers in world, with a high likelihood metastasis and dismal prognosis. The reprogramming glucose metabolism critical development HCC. Warburg effect has recently been confirmed to occur variety cancers, including However, little known about molecular biological mechanisms underlying HCC cells. In this study, we sought better understand how methyltransferase 5, N6‐adenosine (METTL5) controls effect. Methods current quantitative real‐time polymerase chain reaction Western blotting were used detect expression METTL5 tissues cell lines. Several different models animal established determine role mechanism Glutathione‐S‐transferase pulldown, coimmunoprecipitation, RNA sequencing, non‐targeted metabolomics, polysome profiling, luciferase reporter assays performed investigate Results We discovered that drove metabolic promote proliferation Mechanistically, upregulation promoted c‐Myc stability thus activated its downstream glycolytic genes lactate dehydrogenase A ( LDHA ), enolase 1 ENO1 triosephosphate isomerase TPI1 solute carrier family 2 member SLC2A1 pyruvate kinase M2 PKM2 ). c‐Box ubiquitin binding domain (UBA) regions specific peptidase 5 (USP5) binded protein inhibited K48‐linked polyubiquitination c‐Myc. Further study revealed controled USP5 translation process, which turn regulated ubiquitination Furthermore, identified cAMP responsive element (CREB1)/P300 as transcriptional regulator transcription patient‐derived tumor xenograft (PDX) models, adenovirus‐mediated knockout had good antitumor prolonged survival PDX‐bearing mice. Conclusions These findings point novel by CREB1/P300‐METTL5‐USP5‐c‐Myc abnormal promotes growth, suggesting potential therapeutic target prognostic biomarker for

Language: Английский

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Hallmarks of cancer resistance

iScience, Journal Year: 2024, Volume and Issue: 27(6), P. 109979 - 109979

Published: May 15, 2024

This review explores the hallmarks of cancer resistance, including drug efflux mediated by ATP-binding cassette (ABC) transporters, metabolic reprogramming characterized Warburg effect, and dynamic interplay between cells mitochondria. The role stem (CSCs) in treatment resistance regulatory influence non-coding RNAs, such as long RNAs (lncRNAs), microRNAs (miRNAs), circular (circRNAs), are studied. chapter emphasizes future directions, encompassing advancements immunotherapy, strategies to counter adaptive integration artificial intelligence for predictive modeling, identification biomarkers personalized treatment. comprehensive exploration these provides a foundation innovative therapeutic approaches, aiming navigate complex landscape enhance patient outcomes.

Language: Английский

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