Protein disulfide isomerase knockdown-induced cell death is cell-line-dependent and involves apoptosis in MCF-7 cells

Hashida, Tomoyo; Kotake, Yaichiro; Ohta, Shigeru

doi:10.2131/jts.36.1

Cited by 43 publications

(43 citation statements)

References 20 publications

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“…Previously, it was shown that PDI knockdown results in apoptosis in human breast cancer MCF-7 cells and human neuroblastoma SH-SY5Y cells (32). Moreover, a PDI inhibitor, bacitracin, abrogated survival responses to ER stress and enhanced apoptosis caused by ER stress-inducing agents, fenretinide and velcade, in human melanoma cells (5).…”

Section: Discussionmentioning

confidence: 98%

Discovery of an orally active small-molecule irreversible inhibitor of protein disulfide isomerase for ovarian cancer treatment

Butkevich

Yamada

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

190

217

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Protein disulfide isomerase (PDI), an endoplasmic reticulum chaperone protein, catalyzes disulfide bond breakage, formation, and rearrangement. The effect of PDI inhibition on ovarian cancer progression is not yet clear, and there is a need for potent, selective, and safe small-molecule inhibitors of PDI. Here, we report a class of propynoic acid carbamoyl methyl amides (PACMAs) that are active against a panel of human ovarian cancer cell lines. Using fluorescent derivatives, 2D gel electrophoresis, and MS, we established that PACMA 31, one of the most active analogs, acts as an irreversible small-molecule inhibitor of PDI, forming a covalent bond with the active site cysteines of PDI. We also showed that PDI activity is essential for the survival and proliferation of human ovarian cancer cells. In vivo, PACMA 31 showed tumor targeting ability and significantly suppressed ovarian tumor growth without causing toxicity to normal tissues. These irreversible small-molecule PDI inhibitors represent an important approach for the development of targeted anticancer agents for ovarian cancer therapy, and they can also serve as useful probes for investigating the biology of PDIimplicated pathways.oral bioavailability | drug resistance | BODIPY-conjugation

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Section: Discussionmentioning

confidence: 98%

Discovery of an orally active small-molecule irreversible inhibitor of protein disulfide isomerase for ovarian cancer treatment

Butkevich

Yamada

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

190

217

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“…Genetic deletion of PDI is toxic to cells (10,34). The fundamental role of PDI in disulfide bond formation and protein folding raises the question of whether PDI inhibition can be well tolerated.…”

Section: Figurementioning

confidence: 99%

“…However, potential complications of inhibiting PDI are the ubiquitous distribution and critical function of intracellular PDI. Chronic PDI silencing is toxic in cultured cells (10), and PDI-deficient animals have not been developed. In addition, presently available inhibitors of PDI are sulfhydryl-reactive compounds that bind covalently at the CXXC catalytic site (11); are nonselective, acting broadly on thiol isomerases (12); or are cytotoxic (13,14).…”

Section: Introductionmentioning

confidence: 99%

Protein disulfide isomerase inhibitors constitute a new class of antithrombotic agents

Jasuja

Passam²,

Kennedy³

et al. 2012

J. Clin. Invest.

261

345

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Thrombosis, or blood clot formation, and its sequelae remain a leading cause of morbidity and mortality, and recurrent thrombosis is common despite current optimal therapy. Protein disulfide isomerase (PDI) is an oxidoreductase that has recently been shown to participate in thrombus formation. While currently available antithrombotic agents inhibit either platelet aggregation or fibrin generation, inhibition of secreted PDI blocks the earliest stages of thrombus formation, suppressing both pathways. Here, we explored extracellular PDI as an alternative target of antithrombotic therapy. A high-throughput screen identified quercetin-3-rutinoside as an inhibitor of PDI reductase activity in vitro. Inhibition of PDI was selective, as quercetin-3-rutinoside failed to inhibit the reductase activity of several other thiol isomerases found in the vasculature. Cellular assays showed that quercetin-3-rutinoside inhibited aggregation of human and mouse platelets and endothelial cell-mediated fibrin generation in human endothelial cells. Using intravital microscopy in mice, we demonstrated that quercetin-3-rutinoside blocks thrombus formation in vivo by inhibiting PDI. Infusion of recombinant PDI reversed the antithrombotic effect of quercetin-3-rutinoside. Thus, PDI is a viable target for small molecule inhibition of thrombus formation, and its inhibition may prove to be a useful adjunct in refractory thrombotic diseases that are not controlled with conventional antithrombotic agents.

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“…In addition, PDI has also been implicated in a number of cancers (8)(9)(10), HIV-1 pathogenesis (11), and blood clot formation (12), suggesting the growing importance of understanding this enzyme. One challenge has been the lack of available drug-like inhibitors, especially for in vivo evaluation in neurodegenerative disease models.…”

mentioning

confidence: 99%

Small molecule-induced oxidation of protein disulfide isomerase is neuroprotective

Kaplan

Gaschler

Dunn

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Protein disulfide isomerase (PDI) is a chaperone protein in the endoplasmic reticulum that is up-regulated in mouse models of, and brains of patients with, neurodegenerative diseases involving protein misfolding. PDI's role in these diseases, however, is not fully understood. Here, we report the discovery of a reversible, neuroprotective lead optimized compound (LOC)14, that acts as a modulator of PDI. LOC14 was identified using a high-throughput screen of ∼10,000 lead-optimized compounds for potent rescue of viability of PC12 cells expressing mutant huntingtin protein, followed by an evaluation of compounds on PDI reductase activity in an in vitro screen. Isothermal titration calorimetry and fluorescence experiments revealed that binding to PDI was reversible with a K d of 62 nM, suggesting LOC14 to be the most potent PDI inhibitor reported to date. Using 2D heteronuclear single quantum correlation NMR experiments, we were able to map the binding site of LOC14 as being adjacent to the active site and to observe that binding of LOC14 forces PDI to adopt an oxidized conformation. Furthermore, we found that LOC14-induced oxidation of PDI has a neuroprotective effect not only in cell culture, but also in corticostriatal brain slice cultures. LOC14 exhibited high stability in mouse liver microsomes and blood plasma, low intrinsic microsome clearance, and low plasma-protein binding. These results suggest that LOC14 is a promising lead compound to evaluate the potential therapeutic effects of modulating PDI in animal models of disease.small molecule | protein disulfide isomerase | drug | inhibitor | neuroprotection

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Protein disulfide isomerase knockdown-induced cell death is cell-line-dependent and involves apoptosis in MCF-7 cells

Cited by 43 publications

References 20 publications

Discovery of an orally active small-molecule irreversible inhibitor of protein disulfide isomerase for ovarian cancer treatment

Discovery of an orally active small-molecule irreversible inhibitor of protein disulfide isomerase for ovarian cancer treatment

Protein disulfide isomerase inhibitors constitute a new class of antithrombotic agents

Small molecule-induced oxidation of protein disulfide isomerase is neuroprotective

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