HIFs, angiogenesis, and metabolism: elusive enemies in breast cancer

Journal of Clinical Investigation, Год журнала: 2020, Номер 130(10), С. 5074 - 5087

Опубликована: Сен. 1, 2020

Hypoxia-inducible factors (HIFs) and the HIF-dependent cancer hallmarks angiogenesis metabolic rewiring are well-established drivers of breast aggressiveness, therapy resistance, poor prognosis. Targeting HIF its downstream targets in metabolism has been unsuccessful so far clinical setting, with major unresolved challenges residing target selection, development robust biomarkers for response prediction, understanding harnessing escape mechanisms. This Review discusses pathophysiological role HIFs, angiogenesis, targeting these features patients cancer. Rational therapeutic combinations, especially immunotherapy endocrine therapy, seem most promising exploitation intricate interplay cells tumor microenvironment.

Язык: Английский

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Targeting Glutamine Metabolism for Cancer Treatment

Biomolecules & Therapeutics, Год журнала: 2017, Номер 26(1), С. 19 - 28

Опубликована: Дек. 7, 2017

Rapidly proliferating cancer cells require energy and cellular building blocks for their growth ability to maintain redox balance.Many studies have focused on understanding how adapt nutrient metabolism meet the high demand of anabolism required proliferation maintaining balance.Glutamine, most abundant amino acid in plasma, is a well-known used by increase as well survival under metabolic stress conditions.In this review, we provide an overview role glutamine cell highlight mechanisms which affects signaling.Furthermore, summarize potential therapeutic approaches targeting treatment numerous types cancer.

Язык: Английский

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Selective glutamine metabolism inhibition in tumor cells improves antitumor T lymphocyte activity in triple-negative breast cancer

Journal of Clinical Investigation, Год журнала: 2020, Номер 131(4)

Опубликована: Дек. 15, 2020

Rapidly proliferating tumor and immune cells need metabolic programs that support energy biomass production. The amino acid glutamine is consumed by effector T glutamine-addicted triple-negative breast cancer (TNBC) cells, suggesting a competition for may exist within the microenvironment, potentially serving as therapeutic intervention strategy. Here, we report there an inverse correlation between genes markers of cell-mediated cytotoxicity in human basal-like (BLBC) patient data sets, with increased metabolism decreased cell associated poor survival. We found cell-specific loss glutaminase (GLS), key enzyme metabolism, improved antitumor activation both spontaneous mouse TNBC model orthotopic grafts. transporter inhibitor V-9302 selectively blocked uptake but not CD8+ driving synthesis glutathione, major cellular antioxidant, to improve function. propose "glutamine steal" scenario, which deprive tumor-infiltrating lymphocytes needed glutamine, thus impairing responses. Therefore, tumor-selective targeting be promising strategy TNBC.

Язык: Английский

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Targeting glutamine metabolism as a therapeutic strategy for cancer

Experimental & Molecular Medicine, Год журнала: 2023, Номер 55(4), С. 706 - 715

Опубликована: Апрель 3, 2023

Abstract Proliferating cancer cells rely largely on glutamine for survival and proliferation. Glutamine serves as a carbon source the synthesis of lipids metabolites via TCA cycle, well nitrogen amino acid nucleotide synthesis. To date, many studies have explored role metabolism in cancer, thereby providing scientific rationale targeting treatment. In this review, we summarize mechanism(s) involved at each step metabolism, from transporters to redox homeostasis, highlight areas that can be exploited clinical Furthermore, discuss mechanisms underlying cell resistance agents target strategies overcoming these mechanisms. Finally, effects blockade tumor microenvironment explore maximize utility blockers

Язык: Английский

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Metabolic reprogramming toward oxidative phosphorylation identifies a therapeutic target for mantle cell lymphoma

Science Translational Medicine, Год журнала: 2019, Номер 11(491)

Опубликована: Май 8, 2019

Metabolic reprogramming is linked to cancer cell growth and proliferation, metastasis, therapeutic resistance in a multitude of cancers. Targeting dysregulated metabolic pathways overcome resistance, an urgent clinical need all relapsed/refractory cancers, remains difficult. Through genomic analyses specimens, we show that toward oxidative phosphorylation (OXPHOS) glutaminolysis associated with the Bruton's tyrosine kinase inhibitor ibrutinib mantle lymphoma (MCL), B subtype poor outcomes. Inhibition OXPHOS clinically applicable small molecule, IACS-010759, which targets complex I mitochondrial electron transport chain, results marked inhibition vitro vivo ibrutinib-resistant patient-derived models. This work suggests targeting subvert viable approach treat highly refractory malignancies.

Язык: Английский

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Structure and allosteric inhibition of excitatory amino acid transporter 1

Nature, Год журнала: 2017, Номер 544(7651), С. 446 - 451

Опубликована: Апрель 1, 2017

Язык: Английский

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Mitochondria Targeting as an Effective Strategy for Cancer Therapy

International Journal of Molecular Sciences, Год журнала: 2020, Номер 21(9), С. 3363 - 3363

Опубликована: Май 9, 2020

Mitochondria are well known for their role in ATP production and biosynthesis of macromolecules. Importantly, increasing experimental evidence points to the roles mitochondrial bioenergetics, dynamics, signaling tumorigenesis. Recent studies have shown that many types cancer cells, including metastatic tumor therapy-resistant stem reliant on respiration, upregulate oxidative phosphorylation (OXPHOS) activity fuel Mitochondrial metabolism is crucial proliferation, survival, metastasis. OXPHOS dependency has been underlie development resistance chemotherapy radiotherapy. Furthermore, recent demonstrated elevated heme synthesis uptake leads intensified respiration generation, thereby promoting tumorigenic functions non-small cell lung (NSCLC) cells. Also, lowering uptake/synthesis inhibits effectively reduces oxygen consumption, inhibiting migration, growth NSCLC. Besides metabolic changes, dynamics such as fission fusion also altered These alterations render mitochondria a vulnerable target therapy. This review summarizes advances understanding cells contribute tumorigenesis drug resistance. It highlights novel approaches involving targeting

Язык: Английский

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Tumor glycolysis, an essential sweet tooth of tumor cells

Seminars in Cancer Biology, Год журнала: 2022, Номер 86, С. 1216 - 1230

Опубликована: Окт. 28, 2022

Язык: Английский

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Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

Cells, Год журнала: 2019, Номер 8(12), С. 1584 - 1584

Опубликована: Дек. 6, 2019

Cancer cells support their growth and proliferation by reprogramming metabolism in order to gain access nutrients. Despite the heterogeneity genetic mutations that lead tumorigenesis, a common alteration tumors occurs pathways upregulate nutrient acquisition. A central signaling pathway controls metabolic processes is mTOR pathway. The elucidation of regulation functions can be traced discovery natural compound, rapamycin. Studies using rapamycin have unraveled role control cell metabolism. By sensing intracellular status, orchestrates controlling uptake flux through various pathways. rewiring makes it promising target for cancer therapy. Numerous clinical trials are ongoing evaluate efficacy inhibition treatment. Rapamycin analogs been approved treat specific types cancer. Since does not fully inhibit activity, new compounds engineered catalytic activity more potently block its functions. highly pre-clinical studies, early trial results these second generation inhibitors revealed increased toxicity modest antitumor activity. plasticity seemingly enormous capacity malignant salvage nutrients mechanisms make therapy extremely challenging. Therefore, identifying vulnerabilities different would present opportunities rational therapeutic strategies. Understanding how sources metabolized just growing tumor but also other from microenvironment, particular, immune cells, will facilitate design sophisticated effective regimen. In this review, we discuss illuminated studies. We then review key findings lessons learned both studies could provide insights on innovative strategies, including immunotherapy network

Язык: Английский

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Emerging Roles of Energy Metabolism in Ferroptosis Regulation of Tumor Cells

Advanced Science, Год журнала: 2021, Номер 8(22)

Опубликована: Окт. 10, 2021

Abstract Ferroptosis is a new form of regulated cell death, which characterized by the iron‐dependent accumulation lethal lipid peroxides and involved in many critical diseases. Recent reports revealed that cellular energy metabolism activities such as glycolysis, pentose phosphate pathway (PPP), tricarboxylic acid cycle are regulation key ferroptosis markers reduced nicotinamide adenine dinucleotide (NADPH), glutathione (GSH), reactive oxygen species (ROS), therefore imposing potential regulatory roles ferroptosis. Remarkably, tumor cells can activate adaptive metabolic responses to inhibit for self‐preservation upregulation glycolysis PPP. Due rapid proliferation intensified rate, has become target disrupting redox homeostasis induce Based on these emerging insights, impact those‐tumor specific aberrations systematically characterized, rewired glucose compensation through glutamine utilization analyzed underlying molecular mechanisms. Additionally, those ferroptosis‐based therapeutic strategies also discussed exploiting vulnerabilities, may open up avenues treatment clinical context.

Язык: Английский

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