Overcoming cancer chemotherapy resistance by the induction of ferroptosis

Drug Resistance Updates, Journal Year: 2022, Volume and Issue: 66, P. 100916 - 100916

Published: Dec. 29, 2022

Language: Английский

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Cancer-associated fibroblasts suppress ferroptosis and induce gemcitabine resistance in pancreatic cancer cells by secreting exosome-derived ACSL4-targeting miRNAs

Drug Resistance Updates, Journal Year: 2023, Volume and Issue: 68, P. 100960 - 100960

Published: March 28, 2023

Pancreatic cancer continues to be one of the world's most lethal cancers. Chemotherapy resistance in patients with advanced pancreatic often accompany dismal prognosis, highlighting need investigate mechanisms drug and develop therapies overcome chemoresistance.This research was filed Chinese Clinical Trial Registry (ChiCTR2200061320). In order isolate primary normal fibroblasts (NFs) cancer-associated (CAFs) samples ductal adenocarcinoma (PDAC) paracancerous tissue from individuals diagnosed PDAC were obtained. The exosomes obtained using ultracentrifugation, their characteristics determined by Western blotting, nanoparticle tracking analysis, transmission electron microscopy. CAF-derived miRNAs analyzed RT-qPCR high-throughput sequencing. Gemcitabine (GEM) employed promote ferroptosis, ferroptosis levels monitoring lipid reactive oxygen species (ROS), cell survival, intracellular Fe2+ concentrations. To assess vivo tumor response GEM therapy, a xenograft mouse model utilized.Exosomes derived CAFs did not exhibit innate resistance. promoted chemoresistance cells following treatment secreting exosomes, maintaining signaling communication cells. Mechanistically, miR-3173-5p CAF sponged ACSL4 inhibited after uptake cells.This work demonstrates novel mode acquired identifies miR-3173-5p/ACSL4 pathway as promising target for GEM-resistant cancer.

Language: Английский

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miR-124-3p delivered by exosomes from heme oxygenase-1 modified bone marrow mesenchymal stem cells inhibits ferroptosis to attenuate ischemia–reperfusion injury in steatotic grafts

Journal of Nanobiotechnology, Journal Year: 2022, Volume and Issue: 20(1)

Published: April 22, 2022

Abstract Background Steatotic livers tolerate ischemia–reperfusion injury (IRI) poorly, increasing the risk of organ dysfunction. Ferroptosis is considered initiating factor IRI. Heme oxygenase oxygen-1 (HO-1)-modified bone marrow mesenchymal stem cells (BMMSCs) (HO-1/BMMSCs) can reduce hepatic IRI; however, role ferroptosis in IRI steatotic grafts and effect HO-1/BMMSCs-derived exosomes (HM-exos) on remain unknown. Methods A model rat liver transplantation (LT) with a severe donor hypoxia reoxygenation (H/R) hepatocytes were established. Exosomes obtained by differential centrifugation, differentially expressed genes (DEGs) after HM-exo treatment detected using RNA sequencing. The expression markers was analyzed. microRNA (miRNA) sequencing used to analyze miRNA profiles HM-exos. Results We verified candidate H/R treated hepatocytes, observed knockout ferroptosis. In vitro, reduced grafts, enrichment analysis DEGs suggested that HM-exos involved regulation pathway. inhibition hepatocyte injury. contained more abundant miR-124-3p, which H/R-treated inhibiting prostate six transmembrane epithelial antigen 3 (STEAP3), while overexpression Steap3 reversed mir-124-3p. addition, from cell knocked out for miR-124-3p showed weakened inhibitory Similarly, increased content decreasing level STEAP3 reducing degree Conclusion during LT liver. downregulates inhibit ferroptosis, thereby attenuating graft IRI, might be promising strategy treat grafts. Graphical

Language: Английский

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ACSL3 and ACSL4, Distinct Roles in Ferroptosis and Cancers

Cancers, Journal Year: 2022, Volume and Issue: 14(23), P. 5896 - 5896

Published: Nov. 29, 2022

The long-chain fatty acyl CoA synthetase (ACSLs) family of enzymes contributes significantly to lipid metabolism and produces acyl-coenzyme A by catalyzing acid oxidation. dysregulation ACSL3 ACSL4, which belong the five isoforms ACSLs, plays a key role in cancer initiation, development, metastasis, tumor immunity may provide several possible therapeutic strategies. Moreover, ACSL4 are crucial for ferroptosis, non-apoptotic cell death triggered accumulation membrane peroxides due iron overload. Here, we present summary current knowledge on their functions various cancers. Research molecular mechanisms involved regulation ferroptosis is critical developing targeted therapies cancer.

Language: Английский

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Non-coding RNAs and ferroptosis: potential implications for cancer therapy

Cell Death and Differentiation, Journal Year: 2022, Volume and Issue: 29(6), P. 1094 - 1106

Published: April 14, 2022

Abstract Ferroptosis is a recently defined form of regulated cell death, which biochemically and morphologically distinct from traditional forms programmed death such as apoptosis or necrosis. It driven by iron, reactive oxygen species, phospholipids that are oxidatively damaged, ultimately resulting in mitochondrial damage breakdown membrane integrity. Numerous cellular signaling pathways molecules involved the regulation ferroptosis, including enzymes control redox status. Alterations ferroptosis-regulating network can contribute to development various diseases, cancer. Evidence suggests ferroptosis commonly suppressed cancer cells, allowing them survive progress. However, cells resistant common chemotherapeutic drugs seem be highly susceptible inducers, highlighting great potential pharmacologic modulation for treatment. Non-coding RNAs (ncRNAs) considered master regulators processes, particularly where they have been implicated all hallmarks Recent work also demonstrated their involvement molecular ferroptosis. Hence, ncRNA-based therapeutics represent an exciting alternative modulate therapy. This review summarizes ncRNAs highlights underlying mechanisms light therapeutic applications.

Language: Английский

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Ferroptosis in hepatocellular carcinoma: mechanisms and targeted therapy

British Journal of Cancer, Journal Year: 2022, Volume and Issue: 128(2), P. 190 - 205

Published: Oct. 13, 2022

Language: Английский

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Acyl-CoA synthase ACSL4: an essential target in ferroptosis and fatty acid metabolism

Chinese Medical Journal, Journal Year: 2023, Volume and Issue: unknown

Published: July 6, 2023

Long-chain acyl-coenzyme A (CoA) synthase 4 (ACSL4) is an enzyme that esterifies CoA into specific polyunsaturated fatty acids, such as arachidonic acid and adrenic acid. Based on accumulated evidence, the ACSL4-catalyzed biosynthesis of arachidonoyl-CoA contributes to execution ferroptosis by triggering phospholipid peroxidation. Ferroptosis a type programmed cell death caused iron-dependent peroxidation lipids; ACSL4 glutathione peroxidase positively negatively regulate ferroptosis, respectively. In addition, essential regulator (FA) metabolism. remodels composition membranes, regulates steroidogenesis, balances eicosanoid biosynthesis. ACSL4-mediated metabolic reprogramming antitumor immunity have attracted much attention in cancer biology. Because it facilitates cross-talk between FA metabolism, also research hotspot diseases ischemia/reperfusion injuries. this review, we focus structure, biological function, unique role ASCL4 various human diseases. Finally, propose might be potential therapeutic target.

Language: Английский

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A graphical journey through iron metabolism, microRNAs, and hypoxia in ferroptosis

Redox Biology, Journal Year: 2022, Volume and Issue: 54, P. 102365 - 102365

Published: June 10, 2022

Ferroptosis is an iron-dependent form of cell death, which triggered by disturbed membrane integrity due to overproduction lipid peroxides. Induction ferroptosis comprises several alterations, i.e. altered iron metabolism, response oxidative stress, or peroxide production. At the physiological level transcription, translation, and microRNAs add appearance and/or activity building blocks that negatively positively balance ferroptosis. contributes tissue damage in case of, e.g., brain heart injury but may be desirable overcome chemotherapy resistance. For a more complete picture, it crucial also consider cellular microenvironment, during inflammation tumor context dominated hypoxia. This graphical review visualizes basic mechanisms ferroptosis, categorizes general inducers inhibitors puts focus on microRNAs, homeostasis, hypoxia as regulatory components.

Language: Английский

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Inhibition of CDK1 Overcomes Oxaliplatin Resistance by Regulating ACSL4‐mediated Ferroptosis in Colorectal Cancer

Advanced Science, Journal Year: 2023, Volume and Issue: 10(25)

Published: July 10, 2023

Oxaliplatin is a widely used chemotherapy drug for patients with advanced colorectal cancer (CRC); however, frequent resistance limits its therapeutic efficacy in patients. Here, this work identifies cyclin-dependent kinase 1 (CDK1) as critical contributor to oxaliplatin via vitro and vivo CRISPR/Cas9 screening. CDK1 highly expressed oxaliplatin-resistant cells tissues due the loss of N6-methyladenosine modification. Genetic pharmacological blockade restore susceptibility CRC cell/patient-derived xenograft models. Mechanistically, directly binds phosphorylates Acyl-CoA synthetase long-chain family 4 (ACSL4) at S447, followed by recruitment E3 ubiquitin ligase UBR5 polyubiquitination ACSL4 K388, K498, K690, which leads protein degradation. Reduced subsequently blocks biosynthesis polyunsaturated fatty acid containing lipids, thereby inhibiting lipid peroxidation ferroptosis, unique iron-dependent form oxidative cell death. Moreover, treatment ferroptosis inhibitor nullifies enhancement sensitivity vivo. Collectively, findings indicate that confers suppressing ferroptosis. Therefore, administration may be an attractive strategy treat CRC.

Language: Английский

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MiR-20a-5p alleviates kidney ischemia/reperfusion injury by targeting ACSL4-dependent ferroptosis

American Journal of Transplantation, Journal Year: 2023, Volume and Issue: 23(1), P. 11 - 25

Published: Jan. 1, 2023

Language: Английский

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