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Therapeutic Targeting of Protein Disulfide Isomerase PDIA1 in Multiple Myeloma

ABSTRACT: Therapeutic Targeting of Protein Disulfide Isomerase PDIA1 in Multiple Myeloma

PROVIDER: PRJNA702993 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13744543_1.fastq.gz	Fastqsanger.gz
	SRR13744543_2.fastq.gz	Fastqsanger.gz
	SRR13744544_1.fastq.gz	Fastqsanger.gz
	SRR13744544_2.fastq.gz	Fastqsanger.gz
	SRR13744545_1.fastq.gz	Fastqsanger.gz

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Therapeutic Targeting of Protein Disulfide Isomerase PDIA1 in Multiple Myeloma

Project description:Patients with multiple myeloma refractory to standard treatments have short survival. High PDIA1 expression confers resistance to proteasome inhibitors and other stressors due to the gain in ER-function, while maintaining or increasing vulnerability to PDIA1 inhibition. In this study we report the identification and characterization of an orally bioavailable novel PDIA1 inhibitor CCF642-34 that is effective against multiple myeloma in pre-clinical models.

2021-02-20 | GSE167097 | GEO

Therapeutic Targeting of Protein Disulfide Isomerase PDIA1 in Multiple Myeloma.

Project description:Multiple myeloma is a genetically complex hematologic neoplasia in which malignant plasma cells constantly operate at the maximum limit of their unfolded protein response (UPR) due to a high secretory burden of immunoglobulins and cytokines. The endoplasmic reticulum (ER) resident protein disulfide isomerase, PDIA1 is indispensable for maintaining structural integrity of cysteine-rich antibodies and cytokines that require accurate intramolecular disulfide bond arrangement. PDIA1 expression analysis from RNA-seq of multiple myeloma patients demonstrated an inverse relationship with survival in relapsed or refractory disease, supporting its critical role in myeloma persistence. Using a structure-guided medicinal chemistry approach, we developed a potent, orally bioavailable small molecule PDIA1 inhibitor CCF642-34. The inhibition of PDIA1 overwhelms the UPR in myeloma cells, resulting in their apoptotic cell death at doses that do not affect the normal CD34+ hematopoietic stem and progenitor cells. Bortezomib resistance leads to increased PDIA1 expression and thus CCF642-34 sensitivity, suggesting that proteasome inhibitor resistance leads to PDIA1 dependence for proteostasis and survival. CCF642-34 induces acute unresolvable UPR in myeloma cells, and oral treatment increased survival of mice in the syngeneic 5TGM1 model of myeloma. Results support development of CCF642-34 to selectively target the plasma cell program and overcome the treatment-refractory state in myeloma.

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Protective Role for the Disulfide Isomerase PDIA3 in Methamphetamine Neurotoxicity

Project description:Methamphetamine abuse continues to be a worldwide problem, damaging the individual user as well as society. Only minimal information exists on molecular changes in the brain that result from methamphetamine administered in patterns typical of human abusers. In order to investigate such changes, we examined the effect of methamphetamine on the transcriptional profile in brains of monkeys. Gene expression profiling of the caudate and hippocampus identified protein disulfide isomerase family member A3 (PDIA3) to be significantly up-regulated in the animals treated with methamphetamine as compared to saline treated control monkeys. Treatment of primary rat neurons with methamphetamine revealed an up-regulation of PDIA3, showing a direct effect of methamphetamine on neurons to increase PDIA3. In vitro studies using a neuroblastoma cell line demonstrated that PDIA3 expression protects against methamphetamine-induced cell toxicity and methamphetamine-induced intracellular reactive oxygen species production, revealing a neuroprotective role for PDIA3. The current study implicates PDIA3 to be an important cellular neuroprotective mechanism against a toxic drug, and as a potential target for therapeutic investigations. To study the effects of chronic METH effects on the brain

2011-11-15 | E-GEOD-33707 | biostudies-arrayexpress

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Dual roles for a tick protein disulfide isomerase during the life cycle of the Lyme disease agent [I. scapularis]

Project description:To determine whether the influences of Ixodes scapularis protein disulfide isomerase A6 (IsPDIA6) on Borrelia burgdorferi colonization is the result of physiological responses, we performed RNA-sequencing (RNA-seq) to compare the transcriptomes of control (GFP) and IsPDIA6-silenced ticks.

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Expression data from SH-SY5Y neuroblastoma cells treated with the protein disulfide isomerase inhibitor origamicin

Project description:Protein disulfide isomerase (PDI) is associated with many diseases including neurodegenerative disorders like Alzheimer’s disease and, hence, is considered a promising drug target. In this study, we investigate the abscisic acid (ABA)-derived PDI inhibitor origamicin for its neuropharmacological potential. We used microarrays to analyze the global change in gene expression as a result of PDI inhibition in the human neuroblastoma cell line SH-SY5Y

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Protein disulfide isomerase inhibition synergistically enhances the efficacy of sorafenib for hepatocellular carcinoma

Project description:Protein disulfide isomerase inhibition synergistically enhances the efficacy of sorafenib for hepatocellular carcinoma

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