ArticleCell death & disease2013
ERO1α-dependent endoplasmic reticulum-mitochondrial calcium flux contributes to ER stress and mitochondrial permeabilization by procaspase-activating compound-1 (PAC-1).
Article in Cell death & disease, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 30 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
30 citing papers in PubMed, 1 synthesis or guideline pooled it, 48 citations in OpenAlex.
- Pooled it
- A fasting-mimicking environment enhances procaspase-activating compound 1 in 2D and 3D glioma cell models.Cell cycle (Georgetown, Tex.) · 2026Article
- ER Proteotoxic Stress Drives Mitochondrial Dysfunction in Heat-Stressed Intestinal Epithelial Cells.Cells · 2026Article
- Molecular mechanisms attributed to colistin renal proximal tubular epithelial cytotoxicity.Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society · 2025Review
- Forsythoside A protects against Zearalenone-induced cell damage in chicken embryonic fibroblasts via mitigation of endoplasmic reticulum stress.Veterinary research communications · 2024Article
- Thrombotic Alterations under Perinatal Hypoxic Conditions: HIF and Other Hypoxic Markers.International journal of molecular sciences · 2023Review
- Key genes expressed in mitochondria‑endoplasmic reticulum contact sites in cancer (Review).Oncology reports · 2023Review
- Homocysteine facilitates endoplasmic reticulum stress and apoptosis of hepatocytes by suppressing ERO1α expression via cooperation between DNMT1 and G9a.Cell biology international · 2022Article
- ER-mitochondria communication is involved in NLRP3 inflammasome activation under stress conditions in the innate immune system.Cellular and molecular life sciences : CMLS · 2022Article
- Article
- Neuroprotective Effect of 4-Phenylbutyric Acid against Photo-Stress in the Retina.Antioxidants (Basel, Switzerland) · 2021Article
- Procaspase-Activating Compound-1 Synergizes with TRAIL to Induce Apoptosis in Established Granulosa Cell Tumor Cell Line (KGN) and Explanted Patient Granulosa Cell Tumor Cells In Vitro.International journal of molecular sciences · 2021Article
- Structural and Functional Significance of the Endoplasmic Reticulum Unfolded Protein Response Transducers and Chaperones at the Mitochondria-ER Contacts: A Cancer Perspective.Frontiers in cell and developmental biology · 2021Review
- The Mitochondrial-Associated Endoplasmic Reticulum Membrane and Its Role in Diabetic Nephropathy.Oxidative medicine and cellular longevity · 2021Review
- Salubrinal Exposes Anticancer Properties in Inflammatory Breast Cancer Cells by Manipulating the Endoplasmic Reticulum Stress Pathway.Frontiers in oncology · 2021Article
- Mitochondria-Associated Endoplasmic Reticulum Membranes in Breast Cancer.Frontiers in cell and developmental biology · 2021Review
- Role of endoplasmic reticulum oxidase 1α in H9C2 cardiomyocytes following hypoxia/reoxygenation injury.Molecular medicine reports · 2020Article
- A high-throughput real-time in vitro assay using mitochondrial targeted roGFP for screening of drugs targeting mitochondria.Redox biology · 2019Article
- Ceramide Metabolism Balance, a Multifaceted Factor in Critical Steps of Breast Cancer Development.International journal of molecular sciences · 2018Review
- Resveratrol induces autophagy-dependent apoptosis in HL-60 cells.BMC cancer · 2018Article
Corrections and comments
- Erratum issued
Authors and funding
5 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Procaspase-activating compound-1 (PAC-1) is the first direct caspase-activating compound discovered; using an in vitro cell-free system of caspase activation. Subsequently, this compound was shown to induce apoptosis in a variety of cancer cells with promising in vivo antitumor activity in canine lymphoma model. Recently, we have reported its ability to kill drug-resistant, Bcl-2/Bcl-xL overexpressing and Bax/Bak-deficient cells despite the essential requirement of mitochondrial cytochrome c (cyt. c) release for caspase activation, indicating that the key molecular targets of PAC-1 in cancer cells are yet to be identified. Here, we have identified Ero1α-dependent endoplasmic reticulum (ER) calcium leakage to mitochondria through mitochondria-associated ER membranes (MAM) and ER luminal hyper-oxidation as the critical events of PAC-1-mediated cell death. PAC-1 treatment upregulated Ero1α in multiple cell lines, whereas silencing of Ero1α significantly inhibited calcium release from ER and cell death. Loss of ER calcium and hyper-oxidation of ER lumen by Ero1α collectively triggered ER stress. Upregulation of GRP78 and splicing of X-box-binding protein 1 (XBP1) mRNA in multiple cancer cells suggested ER stress as the general event triggered by PAC-1. XBP1 mRNA splicing and GRP78 upregulation confirmed ER stress even in Bax/Bak double knockout and PAC-1-resistant Apaf-1-knockout cells, indicating an induction of ER stress-mediated mitochondrial apoptosis by PAC-1. Furthermore, we identified BH3-only protein p53 upregulated modulator of apoptosis (PUMA) as the key molecular link that orchestrates overwhelmed ER stress to mitochondria-mediated apoptosis, involving mitochondrial reactive oxygen species, in a p53-independent manner. Silencing of PUMA in cancer cells effectively reduced cyt. c release and cell death by PAC-1.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.