Targeting lipid metabolism in metastatic prostate cancer DOI Creative Commons
Tahlia Scheinberg, Blossom Mak, Lisa M. Butler

et al.

Therapeutic Advances in Medical Oncology, Journal Year: 2023, Volume and Issue: 15

Published: Jan. 1, 2023

Despite key advances in the treatment of prostate cancer (PCa), a proportion men have de novo resistance, and all will develop resistance to current therapeutics over time. Aberrant lipid metabolism has long been associated with carcinogenesis progression, but more recently there an explosion preclinical clinical data which is informing new trials. This review explores epidemiological links between obesity metabolic syndrome PCa, evidence for altered circulating lipids PCa their potential role as biomarkers, well novel therapeutic strategies targeting including therapies widely used cardiovascular disease such statins, metformin lifestyle modification, targeted agents sphingosine kinase inhibitors, DES1 inhibitors FASN beta oxidation.

Language: Английский

Targeting ferroptosis opens new avenues for the development of novel therapeutics DOI Creative Commons

Shumin Sun,

Jie Shen, Jianwei Jiang

et al.

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

Published: Sept. 21, 2023

Abstract Ferroptosis is an iron-dependent form of regulated cell death with distinct characteristics, including altered iron homeostasis, reduced defense against oxidative stress, and abnormal lipid peroxidation. Recent studies have provided compelling evidence supporting the notion that ferroptosis plays a key pathogenic role in many diseases such as various cancer types, neurodegenerative disease, involving tissue and/or organ injury, inflammatory infectious diseases. Although precise regulatory networks underlie are largely unknown, particularly respect to initiation progression diseases, recognized bona fide target for further development treatment prevention strategies. Over past decade, considerable progress has been made developing pharmacological agonists antagonists these ferroptosis-related conditions. Here, we provide detailed overview our current knowledge regarding ferroptosis, its pathological roles, regulation during disease progression. Focusing on use chemical tools preclinical studies, also summarize recent advances targeting across growing spectrum ferroptosis-associated Finally, discuss new challenges opportunities potential strategy treating

Language: Английский

Citations

222
Acetyl-CoA metabolism in cancer DOI Creative Commons
David A. Guertin, Kathryn E. Wellen

Nature reviews. Cancer, Journal Year: 2023, Volume and Issue: 23(3), P. 156 - 172

Published: Jan. 19, 2023

Few metabolites can claim a more central and versatile role in cell metabolism than acetyl coenzyme A (acetyl-CoA). Acetyl-CoA is produced during nutrient catabolism to fuel the tricarboxylic acid cycle essential building block for fatty isoprenoid biosynthesis. It also functions as signalling metabolite substrate lysine acetylation reactions, enabling modulation of protein response acetyl-CoA availability. Recent years have seen exciting advances our understanding normal physiology cancer, buoyed by new mouse models, vivo stable-isotope tracing approaches improved methods measuring acetyl-CoA, including specific subcellular compartments. Efforts target metabolic enzymes are advancing, with one therapeutic agent targeting synthesis receiving approval from US Food Drug Administration. In this Review, we give an overview regulation cancer relevance major pathways which participates. We further discuss recent tissues tumours potential these therapeutically. conclude commentary on emerging nodes that may impact biology.

Language: Английский

Citations

129
Inhibition of ATP-citrate lyase improves NASH, liver fibrosis, and dyslipidemia DOI Creative Commons

Marisa R. Morrow,

Battsetseg Batchuluun, Jianhan Wu

et al.

Cell Metabolism, Journal Year: 2022, Volume and Issue: 34(6), P. 919 - 936.e8

Published: June 1, 2022

Language: Английский

Citations

112
Physiological and pathological roles of lipogenesis DOI
Yong Geun Jeon, Ye Young Kim, Gung Lee

et al.

Nature Metabolism, Journal Year: 2023, Volume and Issue: 5(5), P. 735 - 759

Published: May 4, 2023

Language: Английский

Citations

106
Lipids in cancer: a global view of the contribution of lipid pathways to metastatic formation and treatment resistance DOI Creative Commons
Sophie Vasseur, Fabienne Guillaumond

Oncogenesis, Journal Year: 2022, Volume and Issue: 11(1)

Published: Aug. 9, 2022

Abstract Lipids are essential constituents for malignant tumors, as they absolutely required tumor growth and dissemination. Provided by the microenvironment (TME) or cancer cells themselves through activation of de novo synthesis pathways, orchestrate a large variety pro-tumorigenic functions. Importantly, TME cells, especially immune cancer-associated fibroblasts (CAFs) adipocytes (CAAs), also prone to changes in their lipid content, which hinder promote aggressiveness. In this review, we address significant findings contribution progression towards metastatic disease poor response therapeutic treatments. We highlight benefits targeting pathways preclinical models slow down metastasis development overcome chemo-and immunotherapy resistance.

Language: Английский

Citations

105
Targeting protein modifications in metabolic diseases: molecular mechanisms and targeted therapies DOI Creative Commons
Xiumei Wu, Mengyun Xu,

M. Geng

et al.

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

Published: May 27, 2023

The ever-increasing prevalence of noncommunicable diseases (NCDs) represents a major public health burden worldwide. most common form NCD is metabolic diseases, which affect people all ages and usually manifest their pathobiology through life-threatening cardiovascular complications. A comprehensive understanding the will generate novel targets for improved therapies across spectrum. Protein posttranslational modification (PTM) an important term that refers to biochemical specific amino acid residues in target proteins, immensely increases functional diversity proteome. range PTMs includes phosphorylation, acetylation, methylation, ubiquitination, SUMOylation, neddylation, glycosylation, palmitoylation, myristoylation, prenylation, cholesterylation, glutathionylation, S-nitrosylation, sulfhydration, citrullination, ADP ribosylation, several PTMs. Here, we offer review roles pathological consequences, including diabetes, obesity, fatty liver hyperlipidemia, atherosclerosis. Building upon this framework, afford description proteins pathways involved by focusing on PTM-based protein modifications, showcase pharmaceutical intervention preclinical studies clinical trials, future perspectives. Fundamental research defining mechanisms whereby regulate open new avenues therapeutic intervention.

Language: Английский

Citations

97
Key Molecules of Fatty Acid Metabolism in Gastric Cancer DOI Creative Commons
Chunlei Li, Lilong Zhang, Zhendong Qiu

et al.

Biomolecules, Journal Year: 2022, Volume and Issue: 12(5), P. 706 - 706

Published: May 15, 2022

Fatty acid metabolism is closely linked to the progression of gastric cancer (GC), a very aggressive and life-threatening tumor. This study examines molecules, such as Sterol Regulatory Element-Binding Protein 1 (SREBP1), ATP Citrate Lyase (ACLY), Acetyl-CoA Synthases (ACSs), Carboxylase (ACC), Acid Synthase (FASN), Stearoyl-CoA Desaturase (SCD1), CD36, Binding Proteins (FABPs), Carnitine palmitoyltransferase (CPT1), well their latest studies findings in unveil its core mechanism. The major enzymes fatty de novo synthesis are ACLY, ACSs, ACC, FASN, SCD1, while SREBP1 upstream molecule anabolism. absorption mediated by CD36 FABPs, catabolism CPT1. If at all possible, we will discover novel links between prospective target.

Language: Английский

Citations

73
Acetylcarnitine shuttling links mitochondrial metabolism to histone acetylation and lipogenesis DOI Creative Commons
Luke Izzo, Sophie Trefely, Christina Demetriadou

et al.

Science Advances, Journal Year: 2023, Volume and Issue: 9(18)

Published: May 3, 2023

The metabolite acetyl-CoA is necessary for both lipid synthesis in the cytosol and histone acetylation nucleus. two canonical precursors to nuclear-cytoplasmic compartment are citrate acetate, which processed by ATP-citrate lyase (ACLY) acyl-CoA synthetase short-chain 2 (ACSS2), respectively. It unclear whether other substantial routes nuclear-cytosolic exist. To investigate this, we generated cancer cell lines lacking ACLY ACSS2 [double knockout (DKO) cells]. Using stable isotope tracing, show that glucose fatty acids contribute pools DKO cells acetylcarnitine shuttling can transfer two-carbon units from mitochondria cytosol. Further, absence of ACLY, feed acid a carnitine responsive acetyltransferase (CrAT)-dependent manner. data define as an ACLY- ACSS2-independent precursor support acetylation, synthesis, growth.

Language: Английский

Citations

56
Metabolic heterogeneity in cancer DOI
Margherita Demicco, Xiao‐Zheng Liu, Katharina Leithner

et al.

Nature Metabolism, Journal Year: 2024, Volume and Issue: 6(1), P. 18 - 38

Published: Jan. 24, 2024

Language: Английский

Citations

52
Hepatic malonyl-CoA synthesis restrains gluconeogenesis by suppressing fat oxidation, pyruvate carboxylation, and amino acid availability DOI Creative Commons
Stanisław Deja, Justin A. Fletcher, Chai-Wan Kim

et al.

Cell Metabolism, Journal Year: 2024, Volume and Issue: 36(5), P. 1088 - 1104.e12

Published: March 5, 2024

Acetyl-CoA carboxylase (ACC) promotes prandial liver metabolism by producing malonyl-CoA, a substrate for de novo lipogenesis and an inhibitor of CPT-1-mediated fat oxidation. We report that inhibition ACC also produces unexpected secondary effects on metabolism. Liver-specific double ACC1/2 knockout (LDKO) or pharmacologic increased anaplerosis, tricarboxylic acid (TCA) cycle intermediates, gluconeogenesis activating hepatic CPT-1 pyruvate flux in the fed state. Fasting should have marginalized role ACC, but LDKO mice maintained elevated TCA intermediates preserved glycemia during fasting. These were accompanied compensatory induction proteolysis amino supply gluconeogenesis, which was offset protein synthesis feeding. Such adaptations may be related to Nrf2 activity, induced correlated with fasting acids. The findings reveal roles malonyl-CoA provide insight into broader inhibition.

Language: Английский

Citations

20