Targeting human Acyl-CoA:cholesterol acyltransferase as a dual viral and T cell metabolic checkpoint DOI Creative Commons
Nathalie Schmidt, Peter A. C. Wing, Mariana O. Diniz

et al.

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: May 14, 2021

Abstract Determining divergent metabolic requirements of T cells, and the viruses tumours they fail to combat, could provide new therapeutic checkpoints. Inhibition acyl-CoA:cholesterol acyltransferase (ACAT) has direct anti-carcinogenic activity. Here, we show that ACAT inhibition antiviral activity against hepatitis B (HBV), as well boosting protective anti-HBV anti-hepatocellular carcinoma (HCC) cells. reduces CD8 + cell neutral lipid droplets promotes microdomains, enhancing TCR signalling TCR-independent bioenergetics. Dysfunctional HBV- HCC-specific cells are rescued by inhibitors directly ex vivo from human liver tumour tissue respectively, including tissue-resident responses. enhances in vitro responsiveness HBV-specific PD-1 blockade increases functional avidity TCR-gene-modified Finally, regulates HBV particle genesis vitro, with reducing both virions subviral particles. Thus, provides a paradigm checkpoint able constrain but rescue exhausted rendering it an attractive target for cure HBV-related HCC.

Language: Английский

Lipid droplet biogenesis and functions in health and disease DOI Open Access

Armella Zadoorian,

Ximing Du, Hongyuan Yang

et al.

Nature Reviews Endocrinology, Journal Year: 2023, Volume and Issue: 19(8), P. 443 - 459

Published: May 23, 2023

Language: Английский

Citations

266
Mechanisms for Modulating Anoikis Resistance in Cancer and the Relevance of Metabolic Reprogramming DOI Creative Commons
Funmilayo O. Adeshakin, Adeleye O. Adeshakin, Lukman O. Afolabi

et al.

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

Published: March 29, 2021

The attachment of cells to the extracellular matrix (ECM) is hallmark structure–function stability and well-being. ECM detachment in localized tumors precedes abnormal dissemination tumor culminating metastasis. Programmed cell death (PCD) activated during tumorigenesis clear off ECM-detached through “anoikis.” However, cancer develop several mechanisms for abrogating anoikis, thus promoting their invasiveness Specific factors, such as growth proteins, pH, transcriptional signaling pathways, oxidative stress, have been reported drivers anoikis resistance, enhancing proliferation Recent studies highlighted key contributions metabolic enabling bypass anoikis. Therefore, understanding driving resistance could help counteract progression prevent This review elucidates dynamics employed by impede proliferation, invasion, In addition, authors discussed other intermediates (especially amino acids nucleotides) that are less explored, which be crucial

Language: Английский

Citations

190
The diversity and breadth of cancer cell fatty acid metabolism DOI Creative Commons
Shilpa R. Nagarajan, Lisa M. Butler, Andrew J. Hoy

et al.

Cancer & Metabolism, Journal Year: 2021, Volume and Issue: 9(1)

Published: Jan. 7, 2021

Tumor cellular metabolism exhibits distinguishing features that collectively enhance biomass synthesis while maintaining redox balance and homeostasis. These attributes reflect the complex interactions between cell-intrinsic factors such as genomic-transcriptomic regulation cell-extrinsic influences, including growth factor nutrient availability. Alongside glucose amino acid metabolism, fatty supports tumorigenesis disease progression through a range of processes membrane biosynthesis, energy storage production, generation signaling intermediates. Here, we highlight complexity in cancer, various inputs outputs intracellular free pool, numerous ways these pathways influence behavior.

Language: Английский

Citations

147
A Biomimetic Aggregation‐Induced Emission Photosensitizer with Antigen‐Presenting and Hitchhiking Function for Lipid Droplet Targeted Photodynamic Immunotherapy DOI
Xiuli Xu, Guanjun Deng,

Zhihong Sun

et al.

Advanced Materials, Journal Year: 2021, Volume and Issue: 33(33)

Published: July 11, 2021

Abstract Photodynamic therapy (PDT) is a promising alternative approach for effective cancer treatment that associated with an antitumor immune response. However, immunosuppression of the tumor microenvironment limits response induced by PDT. Stimulation and proliferation T cells critical step generating responses depends on efficient presentation antigens co‐stimulatory molecules antigen‐presenting (APCs). Here, biomimetic aggregation‐induced emission (AIE) photosensitizers hitchhiking abilities (DC@AIEdots) are developed coating dendritic cell (DC) membranes nanoaggregates AIEgens. Notably, inner AIE can selectively accumulate in lipid droplets cells, outer membrane facilitate DC@AIEdots onto endogenous enhance delivery efficiency about 1.6 times. Furthermore, stimulate vivo activation trigger system. The potential applications therapeutic agents targeting immunotherapy indicated new drug provided. Lastly, study presents photoactive artificial platform stimulation photodynamic immunotherapy.

Language: Английский

Citations

130
Chenodeoxycholic acid suppresses AML progression through promoting lipid peroxidation via ROS/p38 MAPK/DGAT1 pathway and inhibiting M2 macrophage polarization DOI Creative Commons
Jinting Liu,

Yihong Wei,

Wenbo Jia

et al.

Redox Biology, Journal Year: 2022, Volume and Issue: 56, P. 102452 - 102452

Published: Aug. 30, 2022

Bile acids are steroid synthesized in liver, which essential for fat emulsification, cholesterol excretion and gut microbial homeostasis. However, the role of bile leukemia progression remains unclear. We aim at exploring effects mechanisms chenodeoxycholic acid (CDCA), a type acids, on acute myeloid (AML) progression. Here, we found that CDCA was decreased feces plasma AML patients, positively correlated with diversity microbiota, negatively associated prognosis. further demonstrated suppressed both vivo vitro. Mechanistically, bound to mitochondria cause mitochondrial morphology damage containing swelling reduction cristae, membrane potential elevated calcium level, resulted production excessive reactive oxygen species (ROS). Elevated ROS activated p38 MAPK signaling pathway, collaboratively promoted accumulation lipid droplets (LDs) through upregulating expression diacylglycerol O-acyltransferase 1 (DGAT1). As consequence abundance LDs, peroxidation enhanced cells. Moreover, uncovered inhibited M2 macrophage polarization proliferation-promoting macrophages cells co-cultured experiments. Our findings demonstrate suppresses synergistically promoting LDs via ROS/p38 MAPK/DGAT1 pathway caused by dysfunction inhibiting polarization.

Language: Английский

Citations

82
The Emerging Role of Raman Spectroscopy as an Omics Approach for Metabolic Profiling and Biomarker Detection toward Precision Medicine DOI
Gabriel Cutshaw, Saji Uthaman, Nora Hassan

et al.

Chemical Reviews, Journal Year: 2023, Volume and Issue: 123(13), P. 8297 - 8346

Published: June 15, 2023

Omics technologies have rapidly evolved with the unprecedented potential to shape precision medicine. Novel omics approaches are imperative toallow rapid and accurate data collection integration clinical information enable a new era of healthcare. In this comprehensive review, we highlight utility Raman spectroscopy (RS) as an emerging technology for clinically relevant applications using significant samples models. We discuss use RS both label-free approach probing intrinsic metabolites biological materials, labeled where signal from reporters conjugated nanoparticles (NPs) serve indirect measure tracking protein biomarkers

Language: Английский

Citations

75
ACSL3 regulates lipid droplet biogenesis and ferroptosis sensitivity in clear cell renal cell carcinoma DOI Creative Commons

Timothy D. Klasson,

Edward L. LaGory, Hongjuan Zhao

et al.

Cancer & Metabolism, Journal Year: 2022, Volume and Issue: 10(1)

Published: Oct. 3, 2022

Abstract Background Clear cell renal carcinoma (ccRCC), the predominant subtype of kidney cancer, possesses characteristic alterations to multiple metabolic pathways, including accumulation cytosolic lipid droplets. However, pathways that drive droplet in ccRCC cells and their importance cancer biology remain poorly understood. Methods We sought identify carbon sources necessary for using Oil red O staining isotope-tracing lipidomics. The role acyl-CoA synthetase (ACSL) family members, an important group enzymes, was investigated siRNA drug mediated inhibition. CTB XTT assays were performed determine effect ACSL3 knockdown starvation on viability shRNA used study orthotopic mouse model. relationship between ferroptosis susceptibility controlled metabolism examined FACS-based assays. 5-LOX shown with survival assays, expression level predictive value TCGA data assessed. Results found obtain substrates by metabolizing exogenous serum derived lipids not through de novo lipogenesis. show this fatty acids into droplets requires enzyme 3 (ACSL3) other ACSL proteins. Importantly, genetic or pharmacologic suppression is cytotoxic vitro causes a reduction tumor weight Conversely, inhibition decreases ferroptosis, non-apoptotic form death involving peroxidation. sensitivity also highly dependent composition 5-lipoxygenase (5-LOX), leukotriene producing which produces peroxides have been implicated cancers but ccRCC. Conclusions regulates essential growth. In addition, modulates manner acids. Both functions could be exploited therapy.

Language: Английский

Citations

71
Targeting fatty acid metabolism in glioblastoma DOI Creative Commons
Jason Miska, Navdeep S. Chandel

Journal of Clinical Investigation, Journal Year: 2023, Volume and Issue: 133(1)

Published: Jan. 2, 2023

Glioblastoma (GBM) is a primary tumor of the brain defined by its uniform lethality and resistance to conventional therapies. There have been considerable efforts untangle metabolic underpinnings this disease find novel therapeutic avenues for treatment. An emerging focus in field fatty acid (FA) metabolism, which critical numerous diverse biological processes involved GBM pathogenesis. These can be classified into four broad fates: anabolism, catabolism, regulation ferroptosis, generation signaling molecules. Each fate provides unique perspective we inspect biology gives us road map understanding complicated field. This Review discusses basic, translational, clinical insights each these fates provide contemporary FA GBM. It clear, based on literature, that there are far more questions than answers metabolism GBM, substantial should made complex intractable disease.

Language: Английский

Citations

59
Lipids as mediators of cancer progression and metastasis DOI
Felix C. E. Vogel, Adriano B. Chaves‐Filho, Almut Schulze

et al.

Nature Cancer, Journal Year: 2024, Volume and Issue: 5(1), P. 16 - 29

Published: Jan. 25, 2024

Language: Английский

Citations

50
Lipid droplets: a cellular organelle vital in cancer cells DOI Creative Commons
Yi Jin, Yanjie Tan, Jian Wu

et al.

Cell Death Discovery, Journal Year: 2023, Volume and Issue: 9(1)

Published: July 20, 2023

Abstract Lipid droplets (LDs) are cellular organelles comprising a core of neutral lipids (glycerides, sterols) encased within single phospholipid membrane, responsible for storing surplus and furnishing energy. LDs engage in lipid synthesis, catabolism, transport processes by interacting with other (e.g., endoplasmic reticulum, mitochondria), they play critical roles regulating stress immunity. Recent research has uncovered that an elevated number is hallmark cancer cells, attributable to their enhanced uptake synthesis capacity, stored as LDs. Depletion cells induces apoptosis, prompting the emergence small molecule antitumor drugs targeting or key factors FASN, SCD1) pathway. Advancements LD isolation artificial have demonstrated potential applicability research. extracted from murine adipose tissue incubated lipophilic yield drug-coated LDs, which promote apoptosis cells. Furthermore, been employed biological lenses augment resolution subcellular structures (microfilaments, microtubules), facilitating observation intricate thicker including This review delineates functional metabolic mechanisms encapsulates recent progress LD-centered research, offering novel insights tumor diagnosis treatment.

Language: Английский

Citations

46