Cell Metabolism, Journal Year: 2024, Volume and Issue: 36(3), P. 630 - 647.e8
Published: Feb. 2, 2024
Language: Английский
Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)
Published: March 5, 2024
Abstract Abundant macrophage infiltration and altered tumor metabolism are two key hallmarks of glioblastoma. By screening a cluster metabolic small-molecule compounds, we show that inhibiting glioblastoma cell glycolysis impairs migration lactate dehydrogenase inhibitor stiripentol emerges as the top hit. Combined profiling functional studies demonstrate A (LDHA)-directed extracellular signal-regulated kinase (ERK) pathway activates yes-associated protein 1 (YAP1)/ signal transducer activator transcription 3 (STAT3) transcriptional co-activators in cells to upregulate C-C motif chemokine ligand 2 (CCL2) CCL7, which recruit macrophages into microenvironment. Reciprocally, infiltrating produce LDHA-containing vesicles promote glycolysis, proliferation, survival. Genetic pharmacological inhibition LDHA-mediated tumor-macrophage symbiosis markedly suppresses progression mouse models. Analysis plasma samples patients confirms LDHA its downstream signals potential biomarkers correlating positively with density. Thus, provides therapeutic targets for
Language: Английский
Citations
39
Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)
Published: March 7, 2024
Abstract Despite the successful application of immune checkpoint therapy, no response or recurrence is typical in lung cancer. Cancer stem cells (CSCs) have been identified as a crucial player immunotherapy-related resistance. Ferroptosis, form cell death driven by iron-dependent lipid peroxidation, highly regulated cellular metabolism remolding and has shown to synergistic effects when combined with immunotherapy. Metabolic adaption CSCs drives tumor resistance, yet mechanisms their ferroptosis defense evasion remain elusive. Here, through metabolomics, transcriptomics, epithelial-specific Cpt1a -knockout mouse model, clinical analysis, we demonstrate that CPT1A, key rate-limiting enzyme fatty acid oxidation, acts L-carnitine, derived from tumor-associated macrophages drive ferroptosis-resistance CD8 + T inactivation Mechanistically, CPT1A restrains ubiquitination degradation c-Myc, while c-Myc transcriptionally activates expression. The CPT1A/c-Myc positive feedback loop further enhances antioxidant capacity activating NRF2/GPX4 system reduces amount phospholipid polyunsaturated acids ACSL4 downregulating, thereby suppressing CSCs. Significantly, targeting blockade-induced anti-tumor immunity tumoral tumor-bearing mice. results illustrate potential mechanism-guided therapeutic strategy metabolic vulnerability improve efficacy cancer
Language: Английский
Citations
39
Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)
Published: March 27, 2024
Cellular metabolism is an intricate network satisfying bioenergetic and biosynthesis requirements of cells. Relevant studies have been constantly making inroads in our understanding pathophysiology, inspiring development therapeutics. As a crucial component epigenetics at post-transcription level, RNA modification significantly determines fates, further affecting various biological processes cellular phenotypes. To be noted, immunometabolism defines the metabolic alterations occur on immune cells different stages immunological contexts. In this review, we characterize distribution features, modifying mechanisms functions 8 modifications, including N6-methyladenosine (m6A), N6,2'-O-dimethyladenosine (m6Am), N1-methyladenosine (m1A), 5-methylcytosine (m5C), N4-acetylcytosine (ac4C), N7-methylguanosine (m7G), Pseudouridine (Ψ), adenosine-to-inosine (A-to-I) editing, which are relatively most studied types. Then regulatory roles these diverse health disease contexts comprehensively described, categorized as glucose, lipid, amino acid, mitochondrial metabolism. And highlight regulation modifications immunometabolism, influencing responses. Above all, provide thorough discussion about clinical implications metabolism-targeted therapy immunotherapy, progression modification-targeted agents, its potential RNA-targeted Eventually, give legitimate perspectives for future researches field from methodological requirements, mechanistic insights, to therapeutic applications.
Language: Английский
Citations
33
Molecular Cancer, Journal Year: 2024, Volume and Issue: 23(1)
Published: June 20, 2024
Abstract RNA methylation, a prevalent post-transcriptional modification, has garnered considerable attention in research circles. It exerts regulatory control over diverse biological functions by modulating splicing, translation, transport, and stability. Notably, studies have illuminated the substantial impact of methylation on tumor immunity. The primary types encompass N6-methyladenosine (m6A), 5-methylcytosine (m5C), N1-methyladenosine (m1A), N7-methylguanosine (m7G), 3-methylcytidine (m3C). Compelling evidence underscores involvement regulating microenvironment (TME). By affecting translation stability through "writers", "erasers" "readers", influence dysregulation immune cells factors. Consequently, plays pivotal role immunity mediating various behaviors, encompassing proliferation, invasion, metastasis, etc. In this review, we discussed mechanisms several methylations, providing comprehensive overview their roles underlying within among immunocytes. exploring how these modifications mediate evasion, also examine potential applications immunotherapy. This review aims to provide novel insights strategies for identifying targets advancing cancer immunotherapy efficacy.
Language: Английский
Citations
30
Cell Metabolism, Journal Year: 2024, Volume and Issue: 36(3), P. 630 - 647.e8
Published: Feb. 2, 2024
Language: Английский
Citations
29