A Comprehensive and Robust Multiplex-DIA Workflow Profiles Protein Turnover Regulations Associated with Cisplatin Resistance DOI Creative Commons
Barbora Šalovská, Wenxue Li, Oliver M. Bernhardt

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 31, 2024

Summary Measuring protein turnover is essential for understanding cellular biological processes and advancing drug discovery. The multiplex DIA mass spectrometry (DIA-MS) approach, combined with dynamic SILAC labeling (pulse-SILAC, or pSILAC), has proven to be a reliable method analyzing degradation kinetics. Previous DIA-MS workflows have employed various strategies, including leveraging the highest isotopic channels of peptides enhance detection MS signal pairs clusters. In this study, we introduce an improved robust workflow that integrates novel machine learning strategy channel-specific statistical filtering, enabling adaptation systematic temporal variations in channel ratios. This allows comprehensive profiling throughout pSILAC experiment without relying solely on signals. Additionally, developed KdeggeR , data processing analysis package optimized pSILAC-DIA experiments, which estimates visualizes peptide rates profiles. Our integrative was benchmarked both 2-channel 3-channel standard datasets aneuploid cancer cell model before after cisplatin resistance development demonstrated strong negative correlation between transcript regulation major complex subunits. We also identified specific signatures associated resistance.

Language: Английский

Redox regulation: mechanisms, biology and therapeutic targets in diseases DOI Creative Commons
Bowen Li, Hui Ming, Siyuan Qin

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: March 7, 2025

Redox signaling acts as a critical mediator in the dynamic interactions between organisms and their external environment, profoundly influencing both onset progression of various diseases. Under physiological conditions, oxidative free radicals generated by mitochondrial respiratory chain, endoplasmic reticulum, NADPH oxidases can be effectively neutralized NRF2-mediated antioxidant responses. These responses elevate synthesis superoxide dismutase (SOD), catalase, well key molecules like nicotinamide adenine dinucleotide phosphate (NADPH) glutathione (GSH), thereby maintaining cellular redox homeostasis. Disruption this finely tuned equilibrium is closely linked to pathogenesis wide range Recent advances have broadened our understanding molecular mechanisms underpinning dysregulation, highlighting pivotal roles genomic instability, epigenetic modifications, protein degradation, metabolic reprogramming. findings provide foundation for exploring regulation mechanistic basis improving therapeutic strategies. While antioxidant-based therapies shown early promise conditions where stress plays primary pathological role, efficacy diseases characterized complex, multifactorial etiologies remains controversial. A deeper, context-specific signaling, particularly redox-sensitive proteins, designing targeted aimed at re-establishing balance. Emerging small molecule inhibitors that target specific cysteine residues proteins demonstrated promising preclinical outcomes, setting stage forthcoming clinical trials. In review, we summarize current intricate relationship disease also discuss how these insights leveraged optimize strategies practice.

Language: Английский

Citations

4
Unraveling the underlying mechanisms of cancer stem cells in therapeutic resistance for optimizing treatment strategies DOI Creative Commons

Yunhan Tan,

Siyuan Qin, Zhe Zhang

et al.

MedComm – Oncology, Journal Year: 2025, Volume and Issue: 4(1)

Published: Jan. 10, 2025

Abstract The success of cancer therapy has been significantly hampered by various mechanisms therapeutic resistance. Chief among these is the presence clonal heterogeneity within an individual tumor mass. introduction concept stem cells (CSCs)—a rare and immature subpopulation with tumorigenic potential that contributes to intratumoral heterogeneity—has deepened our understanding drug Given characteristics CSCs, such as increased drug‐efflux activity, enhanced DNA‐repair capacity, high metabolic plasticity, adaptability oxidative stress, and/or upregulated detoxifying aldehyde dehydrogenase (ALDH) enzymes, CSCs have recognized a theoretical reservoir for resistant diseases. Implicit in this recognition possibility CSC‐targeted strategies might offer breakthrough overcoming resistance patients. Herein, we summarize generation current underlying CSC‐mediated This extended knowledge progressively translated into novel anticancer enriched available options combination treatments, all which are anticipated improve clinical outcomes patients experiencing CSC‐related relapse.

Language: Английский

Citations

2
Modulation of redox homeostasis: A strategy to overcome cancer drug resistance DOI Creative Commons
Li Yang, Xiaoyue Zhang, Zhihan Wang

et al.

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

Published: March 22, 2023

Cancer treatment is hampered by resistance to conventional therapeutic strategies, including chemotherapy, immunotherapy, and targeted therapy. Redox homeostasis manipulation one of the most effective innovative techniques for overcoming drug resistance. Reactive oxygen species (ROS), previously considered intracellular byproducts aerobic metabolism, are now known regulate multiple signaling pathways as second messengers. cells cope with elevated amounts ROS during therapy upregulating antioxidant system, enabling tumor via a variety mechanisms. In this review, we aim shed light on redox modification that may contribute We summarized molecular mechanisms which signaling-regulated resistance, altered efflux, action targets enhanced DNA damage repair, maintained stemness, reshaped microenvironment. A comprehensive understanding these interrelationships should improve efficacy from fundamental clinical research point view.

Language: Английский

Citations

35
PROTACs: A novel strategy for cancer drug discovery and development DOI Creative Commons
Xin Han, Yi Sun

MedComm, Journal Year: 2023, Volume and Issue: 4(3)

Published: May 29, 2023

Proteolysis targeting chimera (PROTAC) technology has become a powerful strategy in drug discovery, especially for undruggable targets/proteins. A typical PROTAC degrader consists of three components: small molecule that binds to target protein, an E3 ligase ligand (consisting and its recruiter), chemical linker hooks first two components together. In the past 20 years, we have witnessed advancement multiple degraders into clinical trials anticancer therapies. However, one major challenges is only very limited number recruiters are currently available as targeted protein degradation (TPD), although human genome encodes more than 600 ligases. Thus, there urgent need identify additional effective TPD applications. this review, summarized existing RING-type ubiquitin their act ligands application discovery. We believe review could serve reference future development efficient cancer discovery development.

Language: Английский

Citations

26
Role of protein degradation systems in colorectal cancer DOI Creative Commons
Zihan Cui, Mingqi Cong,

Shengjie Yin

et al.

Cell Death Discovery, Journal Year: 2024, Volume and Issue: 10(1)

Published: March 14, 2024

Abstract Protein degradation is essential for maintaining protein homeostasis. The ubiquitin‒proteasome system (UPS) and autophagy–lysosome are the two primary pathways responsible directly related to cell survival. In malignant tumors, UPS plays a critical role in managing excessive load caused by cancer cells hyperproliferation. this review, we provide comprehensive overview of dual roles played autolysosome colorectal (CRC), elucidating their impact on initiation progression disease while also highlighting compensatory relationship. Simultaneously targeting both offers new promise enhancing treatment efficacy against CRC. Additionally, apoptosis closely linked ubiquitination autophagy, caspases degrade proteins. A thorough comprehension interplay between various highly important clarifying mechanism underlying onset

Language: Английский

Citations

15
A region-confined PROTAC nanoplatform for spatiotemporally tunable protein degradation and enhanced cancer therapy DOI Creative Commons
Jing Gao, Xingyu Jiang,

Shumin Lei

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Aug. 4, 2024

The antitumor performance of PROteolysis-TArgeting Chimeras (PROTACs) is limited by its insufficient tumor specificity and poor pharmacokinetics. These disadvantages are further compounded heterogeneity, especially the presence cancer stem-like cells, which drive growth relapse. Herein, we design a region-confined PROTAC nanoplatform that integrates both reactive oxygen species (ROS)-activatable hypoxia-responsive prodrugs for precise manipulation bromodomain extraterminal protein 4 expression eradication. nanoparticles selectively accumulate within penetrate deep into tumors via response to matrix metalloproteinase-2. Photoactivity then reactivated in acidic intracellular milieu discharged due ROS generated photodynamic therapy specifically normoxic microenvironment. Moreover, latent prodrug restored hypoxic cells overexpressing nitroreductase. Here, show ability effectively degrade BRD4 environments, markedly hindering progression breast head-neck models.

Language: Английский

Citations

14
Targeting Wnt Signaling in Cancer Drug Resistance: Insights from Pre-Clinical and Clinical Research DOI
Kiavash Hushmandi, Mina Alimohammadi, Mohammad Heiat

et al.

Pathology - Research and Practice, Journal Year: 2025, Volume and Issue: 267, P. 155837 - 155837

Published: Feb. 11, 2025

Language: Английский

Citations

1
Advancements in Proteolysis Targeting Chimeras for Targeted Therapeutic Strategies in Alzheimer’s Disease DOI Creative Commons

Qiuzhi Zhou,

Weixia Wang, Chunchu Deng

et al.

Molecular Neurobiology, Journal Year: 2025, Volume and Issue: unknown

Published: March 25, 2025

Language: Английский

Citations

1
The ubiquitin-proteasome system in the regulation of tumor dormancy and recurrence DOI
Bashar A. Alhasan, А. В. Морозов, Irina V. Guzhova

et al.

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Journal Year: 2024, Volume and Issue: 1879(4), P. 189119 - 189119

Published: May 16, 2024

Language: Английский

Citations

8
Tumor‐Specific Nano‐Herb Delivery System with High L‐Arginine Loading for Synergistic Chemo and Gas Therapy against Cervical Cancer DOI
Lihua Chen, Hui Ming, Bowen Li

et al.

Small, Journal Year: 2024, Volume and Issue: 20(45)

Published: Aug. 5, 2024

Abstract Cancer metastasis poses significant challenges in current clinical therapy. Osthole (OST) has demonstrated efficacy treating cervical cancer and inhibiting metastasis. Despite these positive results, its limited solubility, poor oral absorption, low bioavailability, photosensitivity hinder application. To address this limitation, a glutathione (GSH)‐responded nano‐herb delivery system (HA/MOS@OST&L‐Arg nanoparticles, HMOA NPs) is devised for the targeted of OST with cascade‐activatable nitric oxide (NO) release. The NPs engineered utilizing enhanced permeability retention (EPR) effects active targeting mediated by hyaluronic acid (HA) binding to glycoprotein CD44. cargoes, including L‐Arginine (L‐Arg), are released rapidly due degradation GSH‐responsive mesoporous organic silica (MOS). Then abundant reactive oxygen species (ROS) produced from presence high concentrations NAD(P)H quinone oxidoreductase 1 (NQO1), resulting generation NO subsequently highly toxic peroxynitrite (ONOO − ) catalyzing guanidine groups L‐Arg. These ROS, NO, ONOO molecules have direct impact on mitochondrial function reducing membrane potential adenosine triphosphate (ATP) production, thereby promoting increased apoptosis Overall, results indicated that great as promising alternative treatment cancer.

Language: Английский

Citations

8