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The anticancer Ruthenium drug BOLD-100 regulates apoptosis of BRAFMT colorectal cancer cells through modulation of the AhR/ROS/ATR signalling axis.

ABSTRACT: The anticancer Ruthenium drug BOLD-100 regulates apoptosis of BRAFMT colorectal cancer cells through modulation of the AhR/ROS/ATR signalling axis.

PROVIDER: PRJNA1062832 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27474455_1.fastq.gz	Fastqsanger.gz
	SRR27474455_2.fastq.gz	Fastqsanger.gz
	SRR27474456_1.fastq.gz	Fastqsanger.gz
	SRR27474456_2.fastq.gz	Fastqsanger.gz
	SRR27474457_1.fastq.gz	Fastqsanger.gz

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The anticancer Ruthenium drug BOLD-100 regulates apoptosis of BRAFMT colorectal cancer cells through modulation of the AhR/ROS/ATR signalling axis.

Project description:The understanding of how oncogenes modulate the mechansim of action of compounds relies on interrogating acute and longer transcriptional changes following treatment. We report here the transcriptional profiles of an isogenic cell line model VACO432 (BRAFMT V600E/WT) and VT1 (BRAFWT/-) following 3H and 24H treatment with a novel ruthenium compound BOLD-100. We compare the two cell line models based on their BRAF status to identify transcriptional changes modulted by oncogenic BRAF.

2024-01-10 | GSE252858 | GEO

Interaction with ribosomal proteins accompanies ER stress-induction of the anticancer metallodrug BOLD-100/KP1339

Project description:The ruthenium-based anticancer agent BOLD-100/KP1339 has shown promising results in several in vitro and in vivo tumour models, as well as in early clinical trials. However, its mode of action remains to be fully elucidated. Recent evidence identified ER stress-induction and concomitant down-modulation of HSPA5 (GRP78) as key drug effects. By exploiting the naturally formed adduct between BOLD-100 and human serum albumin as an immobilization strategy, we were able to perform target profiling experiments that revealed the ribosomal proteins RPL10, RPL24 and the transcription factor GTF2I as potential interactors of this ruthenium(III) anticancer agent. Integrating these findings with proteomic profiling and transcriptomic experiments supported ribosomal disturbance and concomitant induction of endoplasmic reticulum (ER) stress. The formation of poly-ribosomes and ER swelling of treated cancer cells by electron microscopy validated this finding. Thus, the direct interaction of BOLD-100 with ribosomal proteins seems to accompany ER stress-induction and modulation of GRP78 in cancer cells.

2021-06-01 | PXD022449 | Pride

BOLD-100 in Combination With FOLFOX for the Treatment of Advanced Solid Tumours

Project description:BOLD-100 is an intravenously administered sterile solution containing the ruthenium-based small molecule. BOLD-100 has been shown to preferentially decrease the expression of GRP78 in tumour cells and ER stressed cells when compared to normal cells. BOLD-100 will be combined with cytotoxic FOLFOX chemotherapy in this study, with a dose escalation cohort to ensure tolerability and safety, followed by a cohort expansion phase.

| 2341799 | ecrin-mdr-crc

Ruthenium Drug BOLD-100 Regulates BRAFMT Colorectal Cancer Cell Apoptosis through AhR/ROS/ATR Signaling Axis Modulation.

Project description:Patients with class I V600EBRAF-mutant (MT) colorectal cancer exhibit a poor prognosis, and their response to combined anti-BRAF/EGFR inhibition remains limited. An unmet need exits for further understanding the biology of V600EBRAFMT colorectal cancer. We used differential gene expression of BRAFWT and MT colorectal cancer cells to identify pathways underpinning BRAFMT colorectal cancer. We tested a panel of molecularly/genetically subtyped colorectal cancer cells for their sensitivity to the unfolded protein response (UPR) activator BOLD-100. To identify novel combination strategies for BOLD-100, we performed RNA sequencing and high-throughput drug screening. Pathway enrichment analysis identified significant enrichment of the UPR and DNA repair pathways in BRAFMT colorectal cancer. We found that oncogenic BRAF plays a crucial role in mediating the response to BOLD-100. Using a systems biology approach, we identified V600EBRAFMT-dependent activation of the replication stress response kinase ataxia telangiectasia and Rad3-related (ATR) as a key mediator of resistance to BOLD-100. Further analysis identified acute increases in BRAFMT-dependent-reactive oxygen species levels following treatment with BOLD-100, which promoted ATR/CHK1 activation and apoptosis. Furthermore, activation of reactive oxygen species/ATR/CHK1 following BOLD-100 was mediated through the AhR transcription factor and CYP1A1. Importantly, pharmacological blockade of this resistance pathway with ATR inhibitors synergistically increased BOLD-100-induced apoptosis and growth inhibition in BRAFMT models. These results highlight a possible novel therapeutic opportunity for BRAFMT colorectal cancer. Implications: BOLD-100 induces BRAFMT-dependent replication stress, and targeted strategies against replication stress (e.g., by using ATR inhibitors) in combination with BOLD-100 may serve as a potential novel therapeutic strategy for clinically aggressive BRAFMT colorectal cancer.

| S-EPMC7616621 | biostudies-literature

Henricia sp. BOLD:AAB3569

Project description:Henricia sp. BOLD:AAB3569 (seastar)

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Hyperosmotic stress induces 2-cell-like cells through ROS and ATR signaling

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2023-08-15 | GSE231475 | GEO

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Project description:Ruthenium based compound have developed for anticancer therapy Identification of the transcriptomes induced by either cisplatin or a ruthenium-based compound (RDC) that are both cytotoxic. Cells were treated with either cisplatin or RDC at their IC50 and for 6h or 24h.

2015-03-05 | GSE66493 | GEO

Henricia sp. BOLD:AAB3569

Project description:Henricia sp. BOLD:AAB3569 (seastar) genomic and transcriptomic data

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Transcription profiling of shoot apices from Arabidopsis wild type, teb, atr, and teb atr mutant plants

Project description:Global gene expression patterns were compared among wild-type Col-0, teb, atr, teb atr of A. thaliana using shoot apices.

2008-04-01 | E-MEXP-1329 | biostudies-arrayexpress

Atr

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