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Gene expression of colorectal cancer cells treated with Celastrol or compound 19-048

ABSTRACT: As a terpenoids natural product isolated from the plant Thunder God Vine, Celastrol is widely studied for its pharmacological activities, including anti-tumor activities. However, the clinical application of Celastrol is strictly limited due to its severe side effects. Without identification and validation of the target protein of Celastrol, it is difficult to determine whether its anti-tumor activities and side effects are due to inhibition of the same protein. Using a new computational tool we have developed for target discovery, peroxiredoxin I (PRDX1) was identified as the ROS-manipulating target protein of Celastrol. High-resolution crystal structure revealed the unique binding mode of Celastrol with PRDX1, via covalent reaction to the catalytic Cys-173 residue of PRDX1. New derivative compound named 19-048 with improved potency against PRDX1 and selectivity towards PRDX2~PRDX6 were synthesized. Both Celastrol and compound 19-048 effectively suppressed the proliferation of colorectal cancer cells. While these anti-tumor efficacy was significantly diminished on xenograft nude mice bearing PRDX1 knock-down colorectal cancer cells. Several downstream genes of p53 were dramatically up-regulated in the presence of Celastrol and compound 19-048. Our findings reveal that the side effects of Celastrol could be reduced via structural modification, and PRDX1 inhibition is promising for the treatment of colorectal cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE198630 | GEO | 2022/12/31

REPOSITORIES: GEO

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Celastrol targets LRP1 to inhibit fibroblast-macrophage crosstalk and ameliorates psoriasis progression

Project description:Purpose: This study aimed to explore the mechanism of Celastrol in improving psoriasis through single-cell transcriptomics Methods: Supplementation with intragastric administration of celastrol in C57BL/6 mice to observe its effect on IMQ-induced psoriasis. Single-cell RNA sequencing were performed to explore the role of celastrol for IMQ-induced psoriasis. Results: A natural product library was used to screen for a small molecule compound, celastrol, that could interfere with fibroblast-macrophage communication. It was demonstrated that celastrol targeted low-denisity lipoprotein receptor-related protein 1 (LRP1) to inhibit fibroblast secretion of CCL2 and inhibited psoriasis progression by reducing its recruitment to macrophages, thereby blocking communication between the two cells Conclusion: We report that celastrol targeted low-denisity lipoprotein receptor-related protein 1 (LRP1) to inhibit fibroblast secretion of CCL2 and inhibited psoriasis progression by reducing its recruitment to macrophages. The use of celastrol maybe a noveltherapeuticoption for psoriasis.

2024-04-20 | GSE231728 | GEO

Genome-wide analysis of histone eviction by FAIRE-Seq

Project description:A major class of chemotherapeutics targets topoisomerase II for DNA double-strand breaks and cancer cell elimination. We compare four members of this class?the anthracyclines doxorubicin, daunorubicin and aclarubicin that does not induce DNA breaks?and a different compound, etoposide. We define a novel activity for anthracyclines: histone eviction from open chromosomal areas. Since histone variant H2AX is also evicted, DNA damage response is attenuated when compared to etoposide. Histone eviction also affects the epigenetic code and deregulates the transcriptome in cancer cells and organs such as the heart. Histone eviction by anthracyclines can drive apoptosis of topoisomerase-negative acute myeloid leukemia blasts in patients. Doxo- and daunorubicin combine the activities of two anti-cancer drugs: etoposide for DNA damage and aclarubicin for histone eviction. We define a novel mechanism of action of anti-cancer drugs doxo- and daunorubicin on chromatin biology with profound consequences on DNA damage responses, epigenetics, transcription, side effects and anti-cancer activities. Comparison of histone occupancy of cells or tissues treated with topoisomerase II inhibitors to un-treated ones by FAIRE-seq.

2013-06-04 | E-GEOD-33632 | biostudies-arrayexpress

Simultaneous activation of heat shock and oxidative stress pathways by celastrol

Project description:Stress response pathways allow cells to rapidly sense and respond to deleterious environmental changes, including those caused by pathophysiological disease states. A previous screen for small molecules capable of activating the human heat shock response identified the triterpenoid celastrol as a potent activator of the heat shock transcription factor HSF1. We show here that celastrol likewise activates the homologous Hsf1 of Saccharomyces cerevisiae. Celastrol induced Hsf1 hyperphosphorylation and concurrently activated a synthetic transcriptional reporter as well as endogenous inducible Hsp70 proteins at the same effective concentration seen in mammalian cells. Moreover, celastrol treatment conferred significant resistance to subsequent lethal heat shock. Transcriptional profiling experiments revealed that in addition to Hsf1, celastrol treatment induced the Yap1-dependent oxidant defense regulon. Oxidative stress-responsive genes were likewise induced in mammalian cells, demonstrating that celastrol simultaneously activates two major cellular stress-mediating pathways. As the induction of cellular stress pathways has implications in the treatment of a variety of human diseases including neurodegenerative diosorders, cardiovascular disease and cancer, celastrol thus represents an attractive therapeutic compound. Keywords: single-dose, single time-point gene induction by natural small molecule celastrol compared to heat shock in wild type (BY4741) Saccahromyces cerevisiae

2006-08-26 | GSE5608 | GEO

Simultaneous activation of heat shock and oxidative stress pathways by celastrol

2006-08-26 | GSE5608 | GEO

Genome-wide analysis of histone eviction by FAIRE-Seq

2013-06-04 | GSE33632 | GEO

Nascent RNA sequencing reveals a dynamic global transcriptional response at genes and enhancers to the natural medicinal compound celastrol

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2017-03-22 | GSE96869 | GEO

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Prdx1,a RNA binding protein,regulate inflammatory injury in intracerebral hemorrhage by targeting RNA stability (PRDX1_iRIP-seq)

Project description:We overexpressed Prdx1 in HeLa cells to study Prdx1-regulated genes using RNA-seq technology, followed by bioinformatic analysis of target genes of Prdx1-regulated.In order to find the precise regulatory mechanisms,we performed iRIP-seq experiment in HeLa cell.

2020-04-10 | GSE134504 | GEO

Transcription profiling of human LNCaP cells treated with celastrol or vehicle for 6h

Project description:Celastrol is a natural product that affects LNCaP gene expression by 6h; We used microarrays to detail the global programme of gene expression affected by celastrol treatment at 6h Experiment Overall Design: LNCaP cells were grown to 50% confluency and treated with celastrol for 6h prior to direct Trizol lysis and RNA isolation

2008-11-07 | E-GEOD-5505 | biostudies-arrayexpress

Celastrol targets LRP1 to inhibit fibroblast-macrophage crosstalk and ameliorates psoriasis progression

Project description:In the present study, we analyzed single-cell multi-omics data from psoriasis patients and healthy individuals and found that more fibroblast-macrophage communication was present in the dermis of psoriasis lesions, exacerbating psoriasis progression. A natural product library was used to screen for a small molecule compound, celastrol, that could interfere with fibroblast-macrophage communication. It was demonstrated that celastrol targeted low-denisity lipoprotein receptor-related protein 1 (LRP1) to inhibit fibroblast secretion of CCL2 and inhibited psoriasis progression by reducing its recruitment to macrophages, thereby blocking communication between the two cells. Moreover, conditional knockdown of LRP1 by fibroblasts significantly improved psoriasis in mice, suggesting that LRP1 may be an important target for the treatment of psoriasis.

2024-03-31 | GSE230842 | GEO

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