MELK promotes HCC carcinogenesis through modulating cuproptosis-related gene DLAT-mediated mitochondrial function DOI Creative Commons
Zhipeng Li, Huaxin Zhou,

Xiangyu Zhai

et al.

Cell Death and Disease, Journal Year: 2023, Volume and Issue: 14(11)

Published: Nov. 11, 2023

Abstract Cuproptosis caused by copper overload is mediated a novel regulatory mechanism that differs from previously documented mechanisms regulating cell death. Cells dependent on mitochondrial respiration showed increased sensitivity to ionophore elesclomol induced cuproptosis. Maternal embryonic leucine zipper kinase(MELK) promotes tumorigenesis and tumor progression through the PI3K/mTOR pathway, which exerts its effects partly targeting pyruvate dehydrogenase complex(PDHc) reprogramming morphology function of mitochondria. However, role MELK in cuproptosis remains unclear. Here, we validated elevated expression enhanced activity signaling subsequently promoted Dihydrolipoamide S-Acetyltransferase (DLAT) stabilized function. This effect helped improve respiration, eliminate excessive intracellular reactive oxygen species (ROS), reduce oxidative stress/damage possibility mitochondria-induced fate alternations, ultimately promote HCC. Meanwhile, reduced translocase outer membrane 20(TOM 20) DLAT oligomers. Moreover, above changes HCC were abolished elesclomol. In conclusion, levels cuproptosis-related signature(CRS) gene (especially proportion monomer) activating thereby promoting drug resistance, altering function, progression.

Language: Английский

Cuproptosis Induced by ROS Responsive Nanoparticles with Elesclomol and Copper Combined with αPD‐L1 for Enhanced Cancer Immunotherapy DOI
Boda Guo,

Feiya Yang,

Lingpu Zhang

et al.

Advanced Materials, Journal Year: 2023, Volume and Issue: 35(22)

Published: March 14, 2023

Cuproptosis is a new cell death that depends on copper (Cu) ionophores to transport Cu into cancer cells, which induces death. However, existing are small molecules with short blood half-life making it hard enough cells. Herein, reactive oxygen species (ROS)-sensitive polymer (PHPM) designed, used co-encapsulate elesclomol (ES) and form nanoparticles (NP@ESCu). After entering ES Cu, triggered by excessive intracellular ROS, readily released. work in concerted way not only kill cells cuproptosis, but also induce immune responses. In vitro, the ability of NP@ESCu efficiently cuproptosis investigated. addition, change transcriptomes treated explored RNA-Seq. vivo, found mice model subcutaneous bladder cancer, reprograming tumor microenvironment. Additionally, further combined anti-programmed protein ligand-1 antibody (αPD-L1). This study provides first report combining nanomedicine can αPD-L1 for enhanced therapy, thereby providing novel strategy future therapy.

Language: Английский

Citations

225
Cuproptosis: A novel therapeutic target for overcoming cancer drug resistance DOI Creative Commons
Yumin Wang, Yongming Chen, Junjing Zhang

et al.

Drug Resistance Updates, Journal Year: 2023, Volume and Issue: 72, P. 101018 - 101018

Published: Nov. 11, 2023

Cuproptosis is a newly identified form of cell death driven by copper. Recently, the role copper and triggered in pathogenesis cancers have attracted attentions. has garnered enormous interest cancer research communities because its great potential for therapy. Copper-based treatment exerts an inhibiting tumor growth may open door chemotherapy-insensitive tumors. In this review, we provide critical analysis on homeostasis dysregulation development progression cancers. Then core molecular mechanisms cuproptosis discussed, followed summarizing current understanding copper-based agents (copper chelators, ionophores, complexes-based dynamic therapy) treatment. Additionally, summarize emerging data ionophores to subdue chemotherapy resistance different types We also review small-molecule compounds nanoparticles (NPs) that kill cells inducing cuproptosis, which will shed new light anticancer drugs through future. Finally, important concepts pressing questions future should be focused were discussed. This article suggests targeting could novel antitumor therapy strategy overcome drug resistance.

Language: Английский

Citations

94
A Polymeric Hydrogel to Eliminate Programmed Death-Ligand 1 for Enhanced Tumor Radio-Immunotherapy DOI
Wenhao Shen, Pei Pei,

Chonghai Zhang

et al.

ACS Nano, Journal Year: 2023, Volume and Issue: 17(23), P. 23998 - 24011

Published: Nov. 21, 2023

Programmed death-ligand 1 (PD-L1) is a specialized shield on tumor cells that evades the immune system. Even inhibited by PD-L1 antibodies, cycling process constantly transports from inside to outside of cells, facilitating renewal and replenishment cancer cell membrane. Herein, we develop sodium alginate hydrogel consisting elesclomol-Cu galactose induce persistent cuproptosis, leading reduction for radio-immunotherapy colon tumors. First, prefabricated synthesized immobilizing elesclomol onto saccharide chain through coordination with bivalent copper ions (Cu2+), followed incorporation galactose. After implantation into tumors, this can be further cross-linked in presence physiological calcium (Ca2+), resulting formation controlled release elesclomol-Cu2+ (ES-Cu) The effectively induces oligomerization DLAT cuproptosis colorectal cells. Interestingly, radiation-induced upregulation abrogated hydrogel, releasing ES-Cu Consequently, sensitization radiotherapy immunotherapy significantly improved, prolonging survival tumor-bearing mice both local metastatic Our study introduces an approach combines radiotherapy.

Language: Английский

Citations

94
Systematic identification of anticancer drug targets reveals a nucleus-to-mitochondria ROS-sensing pathway DOI Creative Commons
Junbing Zhang,

Claire Simpson,

Jacqueline Berner

et al.

Cell, Journal Year: 2023, Volume and Issue: 186(11), P. 2361 - 2379.e25

Published: May 1, 2023

Language: Английский

Citations

93
Cope with copper: From copper linked mechanisms to copper-based clinical cancer therapies DOI
Xidi Wang, Miao Zhou, Yu Liu

et al.

Cancer Letters, Journal Year: 2023, Volume and Issue: 561, P. 216157 - 216157

Published: April 1, 2023

Language: Английский

Citations

77
Copper homeostasis and cuproptosis in cardiovascular disease therapeutics DOI
Lifang Yang, Pingping Yang, Gregory Y.H. Lip

et al.

Trends in Pharmacological Sciences, Journal Year: 2023, Volume and Issue: 44(9), P. 573 - 585

Published: July 25, 2023

Language: Английский

Citations

64
Identification of copper metabolism-related subtypes and establishment of the prognostic model in ovarian cancer DOI Creative Commons
Songyun Zhao, Xin Zhang, Feng Gao

et al.

Frontiers in Endocrinology, Journal Year: 2023, Volume and Issue: 14

Published: March 6, 2023

Ovarian cancer (OC) is one of the most common and malignant gynecological malignancies in gynecology. On other hand, dysregulation copper metabolism (CM) closely associated with tumourigenesis progression. Here, we investigated impact genes (CMRGs) on prognosis OC, discovered various CM clusters, built a risk model to evaluate patient prognosis, immunological features, therapy response.15 CMRGs affecting OC patients were identified The Cancer Genome Atlas (TCGA). Consensus Clustering was used identify two clusters. lasso-cox methods establish metabolism-related gene prognostic signature (CMRGPS) based differentially expressed GSE63885 cohort as an external validation cohort. Expression score-associated verified by single-cell sequencing quantitative real-time PCR (qRT-PCR). Nomograms visually depict clinical value CMRGPS. Differences traits, immune cell infiltration, tumor mutational load (TMB) between groups also extensively examined. Tumour Immune Dysfunction Rejection (TIDE) Phenotype Score (IPS) validate whether CMRGPS could predict response immunotherapy patients.In TCGA cohorts, clusters that differed significantly terms overall survival (OS) microenvironment. We then created containing 11 confirmed its reliable predictive power for patients. expression score-related validated qRT-PCR. Patients divided into low-risk (LR) high-risk (HR) median score, better LR group. 5-year AUC reached 0.74. Enrichment analysis showed group immune-related pathways. results TIDE IPS group.Our study, therefore, provides valuable tool further guide management tailor treatment offering new insights individualized treatment.

Language: Английский

Citations

63
Copper in cancer: from limiting nutrient to therapeutic target DOI Creative Commons
Xiaolong Tang,

Zaihua Yan,

Yandong Miao

et al.

Frontiers in Oncology, Journal Year: 2023, Volume and Issue: 13

Published: June 23, 2023

As an essential nutrient, copper’s redox properties are both beneficial and toxic to cells. Therefore, leveraging the characteristics of copper-dependent diseases or using copper toxicity treat copper-sensitive may offer new strategies for specific disease treatments. In particular, concentration is typically higher in cancer cells, making a critical limiting nutrient cell growth proliferation. Hence, intervening metabolism cells become potential tumor treatment strategy, directly impacting metastasis. this review, we discuss body summarize research progress on role promoting inducing programmed death Additionally, elucidate copper-related drugs treatment, intending provide perspectives treatment.

Language: Английский

Citations

54
A Self‐Amplifying ROS‐Responsive Nanoplatform for Simultaneous Cuproptosis and Cancer Immunotherapy DOI Creative Commons
Hangyi Wu, Zhenhai Zhang, Yanni Cao

et al.

Advanced Science, Journal Year: 2024, Volume and Issue: 11(23)

Published: April 3, 2024

Abstract Cuproptosis is an emerging cell death pathway that depends on the intracellular Cu ions. Elesclomol (ES) as efficient ionophore can specifically transport into mitochondria and trigger cuproptosis. However, ES be rapidly removed metabolized during intravenous administration, leading to a short half‐life limited tumor accumulation, which hampers its clinical application. Here, study develops reactive oxygen species (ROS)‐responsive polymer (PCP) based cinnamaldehyde (CA) polyethylene glycol (PEG) encapsulate ES‐Cu compound (EC), forming ECPCP. ECPCP significantly prolongs systemic circulation of EC enhances accumulation. After cellular internalization, PCP coating stimulatingly dissociates exposing high‐level ROS, releases Cu, thereby triggering via Meanwhile, 2+ ‐stimulated Fenton‐like reaction together with CA‐stimulated ROS production simultaneously breaks redox homeostasis, compensates for insufficient oxidative stress treated alone, in turn inducing immunogenic cells, achieving simultaneous cuproptosis immunotherapy. Furthermore, excessive accelerates stimuli‐dissociation ECPCP, positive feedback therapy loop against self‐alleviation. Therefore, nanoplatform immunotherapy improves dual antitumor mechanism provides potential optimization

Language: Английский

Citations

42
Stimulus‐Responsive Copper Complex Nanoparticles Induce Cuproptosis for Augmented Cancer Immunotherapy DOI Creative Commons

Fuzhen Hu,

Jia Huang,

Tiejun Bing

et al.

Advanced Science, Journal Year: 2024, Volume and Issue: 11(13)

Published: Jan. 25, 2024

Abstract Cuproptosis, an emerging form of programmed cell death, has received tremendous attention in cancer therapy. However, the efficacy cuproptosis remains limited by poor delivery efficiency copper ion carriers. Herein, complex nanoparticles (denoted as Cu(I) NP) are developed that can efficiently deliver into cells to induce cuproptosis. NP demonstrate stimulus‐responsive release complexes, which results mitochondrial dysfunction and promotes aggregation lipoylated dihydrolipoamide S‐acetyltransferase (DLAT), leading Notably, not only cuproptosis, but also elicit robust immune responses suppress tumor growth. Overall, this study provides a promising strategy for cuproptosis‐based

Language: Английский

Citations

39