PROTAC: An Effective Targeted Protein Degradation Strategy for Cancer Therapy

Frontiers in Pharmacology, Journal Year: 2021, Volume and Issue: 12

Published: May 7, 2021

Proteolysis targeting chimeric (PROTAC) technology is an effective endogenous protein degradation tool developed in recent years that can ubiquitinate the target proteins through ubiquitin-proteasome system (UPS) to achieve effect on tumor growth. A number of literature studies PROTAC have proved insight into feasibility degrade proteins. Additionally, first oral PROTACs (ARV-110 and ARV-471) shown encouraging results clinical trials for prostate breast cancer treatment, which inspires a greater enthusiasm research. Here we focus structures mechanisms describe several classes degraders based E3 ligases.

Language: Английский

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LINC02273 drives breast cancer metastasis by epigenetically increasing AGR2 transcription

Molecular Cancer, Journal Year: 2019, Volume and Issue: 18(1)

Published: Dec. 1, 2019

The majority of breast cancer patients die metastasis rather than primary tumors, whereas the molecular mechanisms orchestrating remains poorly understood. Long noncoding RNAs (lncRNA) have been shown to regulate occurrence and progression. However, lncRNAs that drive in their underlying are still largely unknown.lncRNAs highly expressed metastatic lymph nodes were identified by microarray. Survival analysis made Kaplan-Meier method. Cell proliferation, migration, invasion assay was performed confirm phenotype LINC02273. Tail vein model mammary fat pad used for vivo study. RNA pull-down RIP interaction hnRNPL Chromatin isolation purification followed sequencing (ChIRP-seq), RNA-seq, ChIP-seq, luciferase reporter reveal hnRNPL-LINC02273 regulates AGR2. Antisense oligonucleotides treatment.We a novel long LINC02273, whose expression significantly elevated lesions compared genetic screen matched tumor samples. Increased LINC02273 promoted vitro vivo. We further showed stabilized hnRNPL, protein increased lesions, cells. Mechanistically, formed complex which activated AGR2 transcription metastasis. recruitment promoter region epigenetically upregulated augmenting local H3K4me3 H3K27ac levels. Combination an independent prognostic factor predicting patient survival. Moreover, our data revealed LINC02273-targeting antisense (ASO) substantially inhibited vivo.Our findings uncover key role LINC02273-hnRNPL-AGR2 axis provide potential therapeutic targets intervention.

Language: Английский

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Necroptosis-Related lncRNAs: Predicting Prognosis and the Distinction between the Cold and Hot Tumors in Gastric Cancer

Journal of Oncology, Journal Year: 2021, Volume and Issue: 2021, P. 1 - 16

Published: Nov. 8, 2021

In the face of poor prognosis and immunotherapy failure gastric cancer (GC), this project tried to find new potential biomarkers for predicting precision medication ameliorate situation. To form synthetic matrices, we retrieved stomach adenocarcinoma transcriptome data from Genotype-Tissue Expression Project (GTEx) The Cancer Genome Atlas (TCGA). Necroptosis-related prognostic lncRNA was identified by coexpression analysis univariate Cox regression. Then performed least absolute shrinkage selection operator (LASSO) construct necroptosis-related model. Next, Kaplan-Meier analysis, time-dependent receiver operating characteristics (ROC), (uni-Cox) regression, multivariate (multi-Cox) nomogram, calibration curves were made verify evaluate Gene set enrichment analyses (GSEA), principal component (PCA), immune prediction half-maximal inhibitory concentration (IC50) in risk groups also analyzed. For further discussing between cold hot tumors, divided entire into two clusters based on lncRNAs. We constructed a model with 16 model, found plots showed good concordance prediction. area's 1-, 2-, 3-year OS under ROC curve (AUC) 0.726, 0.763, 0.770, respectively. Risk could be guide systemic treatment because significantly different IC50 groups. Above all, help distinguish tumors effectively contribute precise mediation. Cluster 2 as tumor more susceptible immunotherapeutic drugs. results supported that lncRNAs predict make distinction improving individual therapy GC.

Language: Английский

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RNA m6A demethylase FTO-mediated epigenetic up-regulation of LINC00022 promotes tumorigenesis in esophageal squamous cell carcinoma

Journal of Experimental & Clinical Cancer Research, Journal Year: 2021, Volume and Issue: 40(1)

Published: Sept. 20, 2021

Long non-coding RNA (LncRNA) controls cell proliferation and plays a significant role in the initiation progression of esophageal squamous carcinoma (ESCC). N6-methyladenosine (m6A) modification now is recognized as master driver function to maintain homeostasis cancer cells. However, how m6A regulates LncRNA its tumorigenesis ESCC remain unclear.Multiple datasets were used analyze gene expression tumor tissues normal tissues. Kaplan-Meier method ROC curve conducted evaluate prognostic value diagnostic LINC00022 ESCC, respectively. Both gain-of-function loss-of-function experiments employed investigate effects on growth vitro vivo. Bioinformatics analysis, colorimetric assay, RIP, MeRIP co-IP was performed explore epigenetic mechanism up-regulation ESCC.Here we report that demethylation by fat mass obesity-associated protein (FTO) promotes Clinically, revealed up-regulated primary samples predictive poor clinical outcome for patients. Mechanistically, directly binds p21 ubiquitination-mediated degradation, thereby facilitating cell-cycle proliferation. Further, elevated FTO decreased methylation transcript, leading inhibition decay via reader YTHDF2. Over-expression shown drive LINC00022-dependent ESCC.Thus, this study demonstrated m6A-mediated contributes LINC00022, specific target m6A, serves potential biomarker malignancy.

Language: Английский

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Long non-coding RNAs: Biogenesis, functions, and clinical significance in gastric cancer

Molecular Therapy — Oncolytics, Journal Year: 2021, Volume and Issue: 23, P. 458 - 476

Published: Nov. 11, 2021

Gastric cancer (GC) is one of the most prevalent malignant tumor types and third leading cause cancer-related death worldwide. Its morbidity mortality are very high due to a lack understanding about its pathogenesis slow development novel therapeutic strategies. Long non-coding RNAs (lncRNAs) class with length more than 200 nt. They play crucial roles in wide spectrum physiological pathological processes by regulating expression genes involved proliferation, differentiation, apoptosis, cell cycle, invasion, metastasis, DNA damage, carcinogenesis. The aberrant lncRNAs has been found various types. A growing amount evidence demonstrates that many aspects GC pathogenesis, including occurrence, recurrence, indicating their potential role as biomarkers diagnosis, prognosis, targets GC. This review systematically summarizes biogenesis, biological properties, functions highlights critical clinical significance information may contribute better diagnostics treatments for

Language: Английский

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LncRNA LINC00942 promotes chemoresistance in gastric cancer by suppressing MSI2 degradation to enhance c‐Myc mRNA stability

Clinical and Translational Medicine, Journal Year: 2022, Volume and Issue: 12(1)

Published: Jan. 1, 2022

Language: Английский

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Non-coding RNA in cancer drug resistance: Underlying mechanisms and clinical applications

Frontiers in Oncology, Journal Year: 2022, Volume and Issue: 12

Published: Aug. 17, 2022

Cancer is one of the most frequently diagnosed malignant diseases worldwide, posing a serious, long-term threat to patients’ health and life. Systemic chemotherapy remains first-line therapeutic approach for recurrent or metastatic cancer patients after surgery, with potential effectively extend patient survival. However, development drug resistance seriously limits clinical efficiency ultimately results in treatment failure death. A large number studies have shown that non-coding RNAs (ncRNAs), particularly microRNAs, long RNAs, circular are widely involved regulation resistance. Their dysregulation contributes by modulating expression specific target genes cellular apoptosis, autophagy, efflux, epithelial-to-mesenchymal transition (EMT), stem cells (CSCs). Moreover, some ncRNAs also possess great as efficient, biomarkers diagnosis prognosis well targets patients. In this review, we summarize recent findings on emerging role underlying mechanisms focus their applications treatment. This information will be benefit early prognostic assessments ncRNA-based strategies

Language: Английский

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Metabolomic machine learning predictor for diagnosis and prognosis of gastric cancer

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

Published: Feb. 23, 2024

Gastric cancer (GC) represents a significant burden of cancer-related mortality worldwide, underscoring an urgent need for the development early detection strategies and precise postoperative interventions. However, identification non-invasive biomarkers diagnosis patient risk stratification remains underexplored. Here, we conduct targeted metabolomics analysis 702 plasma samples from multi-center participants to elucidate GC metabolic reprogramming. Our machine learning reveals 10-metabolite diagnostic model, which is validated in external test set with sensitivity 0.905, outperforming conventional methods leveraging protein markers (sensitivity < 0.40). Additionally, our learning-derived prognostic model demonstrates superior performance traditional models utilizing clinical parameters effectively stratifies patients into different groups guide precision Collectively, findings reveal landscape identify two distinct biomarker panels that enable prognosis prediction respectively, thus facilitating medicine GC.

Language: Английский

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Enhanced Photodynamic Therapy Synergizing with Inhibition of Tumor Neutrophil Ferroptosis Boosts Anti‐PD‐1 Therapy of Gastric Cancer

Advanced Science, Journal Year: 2024, Volume and Issue: 11(12)

Published: Jan. 17, 2024

Abstract For tumor treatment, the ultimate goal in therapy is to eliminate primary tumor, manage potential metastases, and trigger an antitumor immune response, resulting complete clearance of all malignant cells. Tumor microenvironment (TME) refers local biological environment solid tumors has increasingly become attractive target for cancer therapy. Neutrophils within TME gastric (GC) spontaneously undergo ferroptosis, this process releases oxidized lipids that limit T cell activity. Enhanced photodynamic (PDT) mediated by di‐iodinated IR780 (Icy7) significantly increases production reactive oxygen species (ROS). Meanwhile, neutrophil ferroptosis can be triggered increased ROS generation TME. In study, a liposome encapsulating both inhibitor Liproxstatin‐1 modified photosensitizer Icy7, denoted LLI, inhibits growth GC. LLI internalizes into MFC cells generate causing immunogenic death (ICD). Simultaneously, liposome‐deliver effectively neutrophils. LLI‐based PDT neutrophil‐targeting immunotherapy synergistically boost anti‐PD‐1 treatment elicit potent systemic response with abscopal effects. conclusion, holds great GC immunotherapy.

Language: Английский

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Journey of PROTAC: From Bench to Clinical Trial and Beyond

Biochemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 10, 2025

Proteolysis-targeting chimeras (PROTACs) represent a transformative advancement in drug discovery, offering method to degrade specific intracellular proteins. Unlike traditional inhibitors, PROTACs are bifunctional molecules that target proteins for elimination, enabling the potential treatment of previously "undruggable" This concept, pioneered by Crews and his team, introduced use small link protein an E3 ubiquitin ligase, inducing ubiquitination subsequent degradation protein. By promoting rather than merely inhibiting function, present novel therapeutic strategy with enhanced specificity effectiveness, especially areas such as cancer neurodegenerative diseases. Since their initial field PROTAC research has rapidly expanded numerous now designed wide range disease-relevant The substantial research, investment, collaboration across academia pharmaceutical industry reflect growing interest PROTACs. Review discusses journey from discovery clinical trials, highlighting advancements challenges. Additionally, recent developments fluorescent photogenic PROTACs, used real-time tracking degradation, presented, showcasing evolving targeted therapy.

Language: Английский

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