Targeting Metabolic Plasticity and Flexibility Dynamics for Cancer Therapy

Cancer Discovery, Journal Year: 2020, Volume and Issue: 10(12), P. 1797 - 1807

Published: Nov. 3, 2020

Cancer cells continuously rewire their metabolism to fulfill need for rapid growth and survival while subject changes in environmental cues. Thus, a vital component of cancer cell lies its metabolic adaptability. The constant demand alterations requires flexibility, that is, the ability utilize different substrates; as well plasticity, process substrates ways. In this review, we discuss how dynamic affect tumor progression consequential implications therapy. SIGNIFICANCE: Recognizing adaptability an entity can lead targeted therapy is expected decrease drug resistance.

Language: Английский

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Targeting Glucose Metabolism to Overcome Resistance to Anticancer Chemotherapy in Breast Cancer

Cancers, Journal Year: 2020, Volume and Issue: 12(8), P. 2252 - 2252

Published: Aug. 12, 2020

Breast cancer (BC) is the most prevalent in women. BC heterogeneous, with distinct phenotypical and morphological characteristics. These are based on their gene expression profiles, which divide into different subtypes, among triple-negative breast (TNBC) subtype aggressive one. The growing interest tumor metabolism emphasizes role of altered glucose driving progression, response to treatment, its therapy resistance. Alterations characterized by increased uptake glucose, hyperactivated glycolysis, decreased oxidative phosphorylation (OXPHOS) component, accumulation lactate. deviations attributed upregulation key glycolytic enzymes transporters metabolic pathway. Key such as hexokinase, lactate dehydrogenase, enolase upregulated, thereby conferring resistance towards drugs cisplatin, paclitaxel, tamoxifen, doxorubicin. Besides, drug efflux detoxification two energy-dependent mechanisms contributing emergence chemotherapy can occur at an early or later stage thus limiting success outcome therapy. Therefore, understanding aberrant tumors link essential. Using combinatory treatment inhibitors, for example, 2-deoxy-D-glucose (2-DG) metformin, showed promising results countering Newer designs conjugated sugars peptides that utilize enhanced cell offer selective efficient delivery cells less toxicity healthy cells. Last but not least, naturally occurring compounds plants defined phytochemicals manifest a approach eradication via suppression essential other compartments associated glycolysis. Their benefits human health open new opportunities therapeutic intervention, either alone combination chemotherapeutic drugs. Importantly, efficacious instruments anticancer suppress events leading chemoresistance Here, we review current knowledge classical various ways target will serve strategy chemosensitizing overcoming BC.

Language: Английский

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EIF4A3-Induced circARHGAP29 Promotes Aerobic Glycolysis in Docetaxel-Resistant Prostate Cancer through IGF2BP2/c-Myc/LDHA Signaling

Cancer Research, Journal Year: 2021, Volume and Issue: 82(5), P. 831 - 845

Published: Dec. 29, 2021

Docetaxel-based chemotherapy is a standard-of-care treatment for metastatic prostate cancer, and chemoresistance remains major challenge in clinical practice. Recent studies have demonstrated that circular RNAs (circRNA) play critical roles the development progression of cancer. However, biological potential functions circRNAs mediating docetaxel-resistant cancer yet to be well elucidated. In this study, we analyzed expression profiles -sensitive cells through RNA sequencing found circARHGAP29 was significantly upregulated cell lines samples. Ectopic triggered docetaxel resistance aerobic glycolysis cells, which reduced by silencing circARHGAP29. Moreover, eukaryotic initiation factor 4A3, bound back-spliced junction site downstream flanking sequence circARHGAP29, induced cyclization cytoplasmic export increased stability lactate dehydrogenase A (LDHA) mRNA strengthening its interaction with insulin-like growth 2 mRNA-binding protein 2, leading enhanced glycolytic metabolism. addition, interacted stabilized c-Myc protein, further LDHA facilitating transcription. These findings reveal crucial function increasing stabilizing mRNA, providing promising therapeutic target cancer.Upregulation novel circRNA, promotes metabolism, suggesting it could prognostic biomarker chemoresistant

Language: Английский

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The Mechanism of Warburg Effect-Induced Chemoresistance in Cancer

Frontiers in Oncology, Journal Year: 2021, Volume and Issue: 11

Published: Sept. 3, 2021

Although chemotherapy can improve the overall survival and prognosis of cancer patients, chemoresistance remains an obstacle due to diversity, heterogeneity, adaptability environmental alters in clinic. To determine more possibilities for therapy, recent studies have begun explore changes metabolism, especially glycolysis. The Warburg effect is a hallmark that refers preference cells metabolize glucose anaerobically rather than aerobically, even under normoxia, which contributes chemoresistance. However, association between glycolysis molecular mechanisms glycolysis-induced unclear. This review describes mechanism from aspects process, signaling pathways, tumor microenvironment, their interactions. understanding how induces may provide new targets concepts therapy.

Language: Английский

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Mitochondrial adaptation in cancer drug resistance: prevalence, mechanisms, and management

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

Published: July 18, 2022

Drug resistance represents a major obstacle in cancer management, and the mechanisms underlying stress adaptation of cells response to therapy-induced hostile environment are largely unknown. As central organelle for cellular energy supply, mitochondria can rapidly undergo dynamic changes integrate signaling pathways provide bioenergetic biosynthetic flexibility cells, which contributes multiple aspects tumor characteristics, including drug resistance. Therefore, targeting therapy overcoming has attracted increasing attention various types cancer. Multiple mitochondrial processes, dynamics, metabolism, apoptotic regulatory machinery, have been demonstrated be potential targets. However, recent insights into revealed complexity structure functions, elusive functions biology, inaccessibility mitochondria, posed challenges clinical application mitochondrial-based therapeutic strategies. discovery both novel mitochondria-targeting agents innovative approaches is urgently required. Here, we review most literature summarize molecular their intricate connection with In addition, an overview emerging strategies target effectively chemoresistance highlighted, emphasis on repositioning delivery approaches, may accelerate compounds therapy.

Language: Английский

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Metabolic reprogramming of oncogene-addicted cancer cells to OXPHOS as a mechanism of drug resistance

Redox Biology, Journal Year: 2018, Volume and Issue: 25, P. 101076 - 101076

Published: Dec. 17, 2018

The ability to selectively eradicate oncogene-addicted tumors while reducing systemic toxicity has endeared targeted therapies as a treatment strategy. Nevertheless, development of acquired resistance limits the benefits and durability such regime. Here we report evidence enhanced reliance on mitochondrial oxidative phosphorylation (OXPHOS) in cancers manifesting therapies. To that effect, describe novel OXPHOS targeting activity small molecule compound, OPB-51602 (OPB). Of note, priori with OPB restored sensitivity Furthermore, cancer cells exhibiting stemness markers also showed selective OPB. Importantly, subset patients who developed secondary EGFR tyrosine kinase inhibitor (TKI), resulted decrease metabolic reduction tumor size. Collectively, show here switch key driver drug cancers. This vulnerability is exploited by inhibitor, which shows promise clinical setting.

Language: Английский

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Flavonoids as an effective sensitizer for anti-cancer therapy: insights into multi-faceted mechanisms and applicability towards individualized patient profiles

The EPMA Journal, Journal Year: 2021, Volume and Issue: 12(2), P. 155 - 176

Published: May 17, 2021

Abstract Cost-efficacy of currently applied treatments is an issue in overall cancer management challenging healthcare and causing tremendous economic burden to societies around the world. Consequently, complex treatment models presenting concepts predictive diagnostics followed by targeted prevention tailored personal patient profiles earn global appreciation as benefiting patient, economy, society at large. In this context, application flavonoids a spectrum compounds their nano-technologically created derivatives extensively under consideration, due multi-faceted anti-cancer effects applicable cost-effective management, primary, secondary, even tertiary prevention. This article analyzes most recently updated data focused on potent capacity promote therapeutic interprets all collected research achievements frame-work predictive, preventive, personalized (3P) medicine. Main pillars considered are: - Predictable anti-neoplastic, immune-modulating, drug-sensitizing effects; Targeted molecular pathways improve outcomes increasing sensitivity cells reversing resistance towards modalities.

Language: Английский

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A highly annotated database of genes associated with platinum resistance in cancer

Oncogene, Journal Year: 2021, Volume and Issue: 40(46), P. 6395 - 6405

Published: Oct. 13, 2021

Platinum-based chemotherapy, including cisplatin, carboplatin, and oxaliplatin, is prescribed to 10-20% of all cancer patients. Unfortunately, platinum resistance develops in a significant number patients determinant clinical outcome. Extensive research has been conducted understand overcome resistance, mechanisms can be categorized into several broad biological processes, (1) regulation drug entry, exit, accumulation, sequestration, detoxification, (2) enhanced repair tolerance platinum-induced DNA damage, (3) alterations cell survival pathways, (4) pleiotropic processes (5) changes the tumor microenvironment. As resource community, we provide comprehensive overview accompanied by manually curated database >900 genes/proteins that have associated with over last 30 years literature. The annotated possible pathways through which genes are related types evidence, hyperlinks literature sources. searchable, downloadable available online at http://ptrc-ddr.cptac-data-view.org .

Language: Английский

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TRPM7 silencing modulates glucose metabolic reprogramming to inhibit the growth of ovarian cancer by enhancing AMPK activation to promote HIF-1α degradation

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

Published: Jan. 31, 2022

Abstract Background Tumor cell metabolic reprogramming is crucial for the malignant behavior of cancer cells by promoting their proliferation. However, little known on how transient receptor potential 7 (TRPM7) modulates in ovarian cancer. Methods The effects TRPM7 silencing transcriptome profile, glucose uptake, lactic acid production, extracellular acidification rate (ECAR), oxygen consumption (OCR), intracellular ROS and ATP levels, NAD+/NADH ratios were examined. impacts levels glycolysis-related HK2, PDK1 oxidative phosphorylation (OXPHOS)-related IDH3B UQCRC1, HIF-1α expression AMPK determined effect activity ubiquitination degradation was investigated cells. Results Compared with control, suppressed proliferation shifting preferable glycolysis to OXPHOS. In parallel, decreased uptake tumor-bearing mice negatively correlated but positively HK2 tissues. Mechanistically, significantly increased protein cancer, particularly from OXPHOS abrogated over-expression impaired inhibiting Moreover, enhanced activation inhibited glycolysis, which promoted degradation. Conclusions shift Hence, may be a therapeutic target intervention

Language: Английский

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Mitochondrial and metabolic alterations in cancer cells

European Journal of Cell Biology, Journal Year: 2022, Volume and Issue: 101(3), P. 151225 - 151225

Published: April 13, 2022

Metabolic alterations have been observed in many cancer types. The deregulated metabolism has thus become an emerging hallmark of the disease, where is frequently rewired to aerobic glycolysis. This led concept "metabolic reprogramming", which therefore extensively studied. Over years, it characterized enhancement glycolysis, key mutations some enzymes TCA cycle, and increased glucose uptake, are used by cells achieve a phenotype" useful gain proliferation advantage. Many studies highlighted detail signaling pathways molecular mechanisms responsible for glycolytic switch. However, glycolysis not only metabolic process that rely on. Oxidative Phosphorylation (OXPHOS), gluconeogenesis or beta-oxidation fatty acids (FAO) may be involved development progression several tumors. In cases, these metabolisms even more crucial than tumor survival. review will focus on contribution survival cancers. We also analyze balance between processes regulated, as well therapeutical approaches can derive from their study.

Language: Английский

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