Epacadostat stabilizes the apo-form of IDO1 and signals a pro-tumorigenic pathway in human ovarian cancer cells DOI Creative Commons
Sofia Rossini, Sara Ambrosino, Claudia Volpi

et al.

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Jan. 25, 2024

The tryptophan-degrading enzyme indoleamine 2,3-dioxygenase 1 (IDO1) is a plastic immune checkpoint molecule that potently orchestrates responses within the tumor microenvironment (TME). As heme-containing protein, IDO1 catalyzes conversion of essential amino acid tryptophan into immunoactive metabolites, called kynurenines. By depleting and enriching TME with kynurenines, catalytic activity shapes an immunosuppressive TME. Accordingly, inducible or constitutive expression in cancer correlates negative prognosis for patients, representing one critical tumor-escape mechanisms. However, clinically trialed inhibitors disappointed expected anti-tumor efficacy. Interestingly, non-enzymatic apo-form still active as transducing capable promoting immunoregulatory phenotype dendritic cells (DCs) well pro-tumorigenic behavior murine melanoma. Moreover, inhibitor epacadostat can induce tolerogenic plasmacytoid DCs, overcoming inhibition IDO1. Based on this recent evidence, plasticity was investigated human ovarian cell line, SKOV-3, constitutively expresses dynamic balance between holo- apo-protein, thus potentially endowed dual function (i.e., enzymatic non-enzymatic). Besides inhibiting activity, persistently stabilizes favoring its tyrosine-phosphorylation association phosphatase SHP-2. In SKOV-3 cells, both these early molecular events activate signaling pathway transduced by which independent contributes to tumorigenic cells. Overall, our findings unveiled new mechanism action target, repositioning stabilizer IDO1, tumor. This could contribute clarify lack effectiveness clinical trials shed light innovative immunotherapeutic strategies tackle target.

Language: Английский

Ferroptosis in cancer: From molecular mechanisms to therapeutic strategies DOI Creative Commons
Qian Zhou,

Yu Meng,

Daishi Li

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: March 8, 2024

Ferroptosis is a non-apoptotic form of regulated cell death characterized by the lethal accumulation iron-dependent membrane-localized lipid peroxides. It acts as an innate tumor suppressor mechanism and participates in biological processes tumors. Intriguingly, mesenchymal dedifferentiated cancer cells, which are usually resistant to apoptosis traditional therapies, exquisitely vulnerable ferroptosis, further underscoring its potential treatment approach for cancers, especially refractory cancers. However, impact ferroptosis on extends beyond direct cytotoxic effect cells. induction not only inhibits but also promotes development due negative anticancer immunity. Thus, comprehensive understanding role crucial successful translation therapy from laboratory clinical applications. In this review, we provide overview recent advancements cancer, covering molecular mechanisms, functions, regulatory pathways, interactions with microenvironment. We summarize applications immunotherapy, radiotherapy, systemic therapy, well inhibition various conditions. finally discuss markers, current challenges future directions cancer.

Language: Английский

Citations

177
To metabolomics and beyond: a technological portfolio to investigate cancer metabolism DOI Creative Commons
Federica Danzi,

Raffaella Pacchiana,

Andrea Mafficini

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: March 22, 2023

Abstract Tumour cells have exquisite flexibility in reprogramming their metabolism order to support tumour initiation, progression, metastasis and resistance therapies. These reprogrammed activities include a complete rewiring of the bioenergetic, biosynthetic redox status sustain increased energetic demand cells. Over last decades, cancer field has seen an explosion new biochemical technologies giving more tools than ever before navigate this complexity. Within cell or tissue, metabolites constitute direct signature molecular phenotype thus profiling concrete clinical applications oncology. Metabolomics fluxomics, are key technological approaches that mainly revolutionized enabling researchers both qualitative mechanistic model cancer. Furthermore, upgrade from bulk single-cell analysis provided unprecedented opportunity investigate biology at cellular resolution allowing depth quantitative complex heterogenous diseases. More recently, advent functional genomic screening allowed identification pathways, processes, biomarkers novel therapeutic targets concert with other allow patient stratification treatment regimens. This review is intended be guide for metabolism, highlighting current emerging technologies, emphasizing advantages, disadvantages potential leading development innovative anti-cancer

Language: Английский

Citations

114
Immune regulation through tryptophan metabolism DOI Creative Commons
Su‐Kil Seo, Byungsuk Kwon

Experimental & Molecular Medicine, Journal Year: 2023, Volume and Issue: 55(7), P. 1371 - 1379

Published: July 3, 2023

Amino acids are fundamental units of molecular components that essential for sustaining life; however, their metabolism is closely interconnected to the control systems cell function. Tryptophan (Trp) an amino acid catabolized by complex metabolic pathways. Several resulting Trp metabolites bioactive and play central roles in physiology pathophysiology. Additionally, various physiological functions mutually regulated gut microbiota intestine coordinately maintain intestinal homeostasis symbiosis under steady state conditions during immune response pathogens xenotoxins. Cancer inflammatory diseases associated with dysbiosis- host-related aberrant inactivation aryl hydrocarbon receptor (AHR), which a several metabolites. In this review, we focus on mechanisms through converges AHR activation modulation function restoration tissue how these processes can be targeted using therapeutic approaches cancer autoimmune diseases.

Language: Английский

Citations

106
Tryptophan Metabolism Acts as a New Anti‐Ferroptotic Pathway to Mediate Tumor Growth DOI Creative Commons
Dong Liu, Chunhui Liang, Bin Huang

et al.

Advanced Science, Journal Year: 2023, Volume and Issue: 10(6)

Published: Jan. 10, 2023

Abstract Emerging evidence reveals that amino acid metabolism plays an important role in ferroptotic cell death. The conversion of methionine to cysteine is well known protect tumour cells from ferroptosis upon starvation through transamination. However, whether acids‐produced metabolites participate independent the pathway largely unknown. Here, authors show tryptophan serotonin (5‐HT) and 3‐hydroxyanthranilic (3‐HA) remarkably facilitate escape distinct cysteine‐mediated inhibition. Mechanistically, both 5‐HT 3‐HA act as potent radical trapping antioxidants (RTA) eliminate lipid peroxidation, thereby inhibiting Monoamine oxidase A (MAOA) markedly abrogates protective effect via degrading 5‐HT. Deficiency MAOA renders cancer resistant treatment. Kynureninase (KYNU), which essential for production, confers death, whereas 3‐hydroxyanthranilate 3,4‐dioxygenase (HAAO) significantly blocks mediated inhibition by consuming 3‐HA. In addition, expression level HAAO positively correlated with peroxidation clinical outcome. Together, findings demonstrate works a new anti‐ferroptotic promote growth, targeting this will be promising therapeutic approach

Language: Английский

Citations

86
Gut microbial metabolite facilitates colorectal cancer development via ferroptosis inhibition DOI
Weiwei Cui, Meng Guo, Dong Liu

et al.

Nature Cell Biology, Journal Year: 2024, Volume and Issue: 26(1), P. 124 - 137

Published: Jan. 1, 2024

Language: Английский

Citations

69
SIRT1 activated by AROS sensitizes glioma cells to ferroptosis via induction of NAD+ depletion-dependent activation of ATF3 DOI Creative Commons
Xi Chen, Zhenchuan Wang, Chen Li

et al.

Redox Biology, Journal Year: 2024, Volume and Issue: 69, P. 103030 - 103030

Published: Jan. 3, 2024

Ferroptosis is a type of programmed cell death resulting from iron overload-dependent lipid peroxidation, and could be promoted by activating transcription factor 3 (ATF3). SIRT1 an enzyme accounting for removing acetylated lysine residues target proteins consuming NAD+, but its role remains elusive in ferroptosis ATF3. In this study, we found was activated during the process RSL3-induced glioma ferroptosis. Moreover, aggravated activator SRT2183, suppressed SIRT inhibitor EX527 or when silenced with siRNA. These indicated sensitized cells to Furthermore, expressional upregulation nuclear translocation Silence ATF3 siRNA attenuated increases ferrous downregulation SLC7A11 GPX4 depletion cysteine GSH. Thus, inducting activation. Mechanistically, activation reinforced decline NAD+ FK866 that inhibit NAD + synthesis via salvage pathway, intracellular maintained at higher level supplement exogenous NAD+. Notably, caused RSL3 enhanced further inhibited EX527. consumption Finally, inducing reactive oxygen species-dependent AROS. Together, our study revealed AROS sensitizes ATF3-dependent inhibition GPX4.

Language: Английский

Citations

23
Thirty years of NRF2: advances and therapeutic challenges DOI
Donna D. Zhang

Nature Reviews Drug Discovery, Journal Year: 2025, Volume and Issue: unknown

Published: March 4, 2025

Language: Английский

Citations

11
Aucubin Promotes BMSCs Proliferation and Differentiation of Postmenopausal Osteoporosis Patients by Regulating Ferroptosis and BMP2 Signalling DOI Creative Commons
Yang Zheng,

Rongtai Sun,

Huan Yang

et al.

Journal of Cellular and Molecular Medicine, Journal Year: 2025, Volume and Issue: 29(2)

Published: Jan. 1, 2025

Postmenopausal osteoporosis (PMOP) is a chronic systemic bone metabolism disorder. Promotion in the patterns of human marrow mesenchymal stem cells (hBMSCs) differentiation towards osteoblasts contributes to alleviating osteoporosis. Aucubin, natural compound isolated from well-known herbal medicine Eucommia, was previously shown possess various pharmacological effects. However, its effects on hBMSCs PMOP patients are unknown. The aim this present research investigate impact and underlying process aucubin cell proliferation osteogenic patients. ability inhibit ferroptosis induced by erastin detected; ROS production, ferrous ion levels, SOD, MDA, GPX activities were tested using commercial kits. Next, ALP staining, ARS RT-qPCR, RNA-sequencing, Western blot applied for determining mRNA protein expression levels associated with osteogenesis hBMSCs. study also explored involvement BMP2/Smads signalling promoting evaluated intervention an ovariectomised rat model. results indicated that significantly inhibited generation oxidative stress protected against Additionally, facilitated activating BMP2/SMADs pathway attenuated progression OVX rats, suggesting potential therapeutic benefit postmenopausal (PMOP).

Language: Английский

Citations

2
Targeting the kynurenine pathway: another therapeutic opportunity in the metabolic crosstalk between cancer and immune cells DOI Creative Commons
Irene Kang, George Theodoropoulos, Medhi Wangpaichitr

et al.

Frontiers in Oncology, Journal Year: 2025, Volume and Issue: 14

Published: Jan. 22, 2025

The pivotal role of metabolic reprogramming in cancer-related drug resistance, through the tryptophan-catabolized kynurenine pathway (KP), has been particularly underscored recent research. This pathway, driven by indoleamine 2,3-dioxygenase 1 (IDO1), facilitates immune evasion and promotes tumor progression fostering an immunosuppressive environment. In Phase III investigation combination IDO1 inhibition with checkpoint inhibitors (ICIs), therapy was not efficacious. this review, we revisit current advances, explore future directions, emphasize importance dual KP rate-limiting enzymes tryptophan 2,3-dioxygenase-2 (TDO2) appropriate patient populations. We propose that may maximize therapeutic potential inhibition. Additionally, delve into complex cellular interactions cancer dependencies within microenvironment (TME). Insights from preclinical studies, clinical trials, promising combinations will be discussed to elucidate promote a clear path forward for direction research outcomes.

Language: Английский

Citations

2
IDO1 inhibits ferroptosis by regulating FTO-mediated m6A methylation and SLC7A11 mRNA stability during glioblastoma progression DOI Creative Commons
Qianting Tian,

Guixue Dan,

Xuyan Wang

et al.

Cell Death Discovery, Journal Year: 2025, Volume and Issue: 11(1)

Published: Jan. 25, 2025

Language: Английский

Citations

2