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Protein disulfide isomerase blocks the interaction of LC3II-PHB2 and promotes mTOR signaling to regulate autophagy and radio/chemo-sensitivity.

ABSTRACT: Protein disulfide isomerase (PDI) is an endoplasmic reticulum (ER) enzyme that mediates the formation of disulfide bonds, and is also a therapeutic target for cancer treatment. Our previous studies found that PDI mediates apoptotic signaling by inducing mitochondrial dysfunction. Considering that mitochondrial dysfunction is a major contributor to autophagy, how PDI regulates autophagy remains unclear. Here, we provide evidence that high expression of PDI in colorectal cancer tumors significantly increases the risk of metastasis and poor prognosis of cancer patients. PDI inhibits radio/chemo-induced cell death by regulating autophagy signaling. Mechanistically, the combination of PDI and GRP78 was enhanced after ER stress, which inhibits the degradation of AKT by GRP78, and eventually activates the mTOR pathway to inhibit autophagy initiation. In parallel, PDI can directly interact with the mitophagy receptor PHB2 in mitochondrial, then competitively blocks the binding of LC3II and PHB2 and inhibits the mitophagy signaling. Collectively, our results identify that PDI can reduce radio/chemo-sensitivity by regulating autophagy, which could be served as a potential target for radio/chemo-therapy.

SUBMITTER: Wang R

PROVIDER: S-EPMC9537141 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Protein disulfide isomerase blocks the interaction of LC3II-PHB2 and promotes mTOR signaling to regulate autophagy and radio/chemo-sensitivity.

Wang Ruru R Shang Yajing Y Chen Bin B Xu Feng F Zhang Jie J Zhang Zhaoyang Z Zhao Xipeng X Wan Xiangbo X Xu An A Wu Lijun L Zhao Guoping G

Cell death & disease 20221006 10

Protein disulfide isomerase (PDI) is an endoplasmic reticulum (ER) enzyme that mediates the formation of disulfide bonds, and is also a therapeutic target for cancer treatment. Our previous studies found that PDI mediates apoptotic signaling by inducing mitochondrial dysfunction. Considering that mitochondrial dysfunction is a major contributor to autophagy, how PDI regulates autophagy remains unclear. Here, we provide evidence that high expression of PDI in colorectal cancer tumors significantl ...[more]

PMID: 36202782

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Project description:BACKGROUND: Protein disulfide isomerase (PDI) is required for thrombus formation. We previously demonstrated that glycosylated quercetin flavonoids such as isoquercetin inhibit PDI activity and thrombus formation in animal models, but whether extracellular PDI represents a viable anticoagulant target in humans and how its inhibition affects blood coagulation remain unknown. METHODS: We evaluated effects of oral administration of isoquercetin on platelet-dependent thrombin generation in healthy subjects and patients with persistently elevated anti-phospholipid antibodies. RESULTS: Following oral administration of 1,000 mg isoquercetin to healthy adults, the measured peak plasma quercetin concentration (9.2 μM) exceeded its IC50 for inhibition of PDI by isoquercetin in vitro (2.5 ± 0.4 μM). Platelet-dependent thrombin generation decreased by 51% in the healthy volunteers compared with baseline (P = 0.0004) and by 64% in the anti-phospholipid antibody cohort (P = 0.015) following isoquercetin ingestion. To understand how PDI affects thrombin generation, we evaluated substrates of PDI identified using an unbiased mechanistic-based substrate trapping approach. These studies identified platelet factor V as a PDI substrate. Isoquercetin blocked both platelet factor Va and thrombin generation with an IC50 of ~5 μM. Inhibition of PDI by isoquercetin ingestion resulted in a 53% decrease in the generation of platelet factor Va (P = 0.001). Isoquercetin-mediated inhibition was reversed with addition of exogenous factor Va. CONCLUSION: These studies show that oral administration of isoquercetin inhibits PDI activity in plasma and diminishes platelet-dependent thrombin generation predominantly by blocking the generation of platelet factor Va. These pharmacodynamic and mechanistic observations represent an important step in the development of a novel class of antithrombotic agents targeting PDI. TRIAL REGISTRATION: Clinicaltrials.gov (NCT01722669) FUNDING: National Heart, Lung, and Blood Institute (U54 HL112302) and Quercegen Pharma.

Project description:Overcoming chemo‑ and radio‑resistance is a major challenge in pancreatic cancer treatment. Therefore, there is an urgent need to discover novel therapeutic approaches to avoid chemo‑ and radio‑resistance in pancreatic cancer. Catechol is a phytochemical found in some fruits and vegetables. A few studies have reported on the potential anticancer effects of pure catechol. The present study aimed to explore the chemo‑ and radio‑sensitizing effects of catechol in Panc‑1 human pancreatic cancer cells. The effects of catechol on Panc‑1 cell proliferation, clonogenic survival, invasion, and migration were assessed using MTT, cell migration, and Transwell invasion assays. The chemo‑ and radio‑sensitizing effects of catechol on Panc‑1 cells were evaluated via MTT assay and flow cytometry. Western blotting was conducted to analyze the expression of proteins involved in several mechanisms induced by catechol in Panc‑1 cells, including growth inhibition, apoptosis, suppression of epithelial‑mesenchymal transition (EMT), and chemo‑ and radio‑sensitizing activities. The results indicated that catechol inhibited proliferation, promoted apoptosis, and suppressed cell migration, invasion, and EMT in Panc‑1 cells in a dose‑dependent manner. Catechol treatment also induced the phosphorylation of AMP‑activated protein kinase (AMPK) with a concomitant reduction in the expression of Hippo signaling pathway components, including Yes‑associated protein, cysteine‑rich angiogenic inducer 61, and connective tissue growth factor. In addition, catechol enhanced the chemosensitivity of Panc‑1 cells to gemcitabine, a commonly used chemotherapy in pancreatic cancer treatment. A combination of catechol and radiation enhanced apoptosis and increased the expression of two radiation‑induced DNA damage markers, p‑ATM and p‑Chk2. Collectively, the present results demonstrated that catechol, a naturally occurring compound, could suppress the proliferation of pancreatic cancer cells, reduce the expression of EMT‑related proteins, and enhance the chemo‑ and radio‑sensitivity of Panc‑1 cells by targeting AMPK/Hippo signaling.

Project description:Ribonucleotide reductase M1 (RRM1), the catalytic subunit of ribonucleotide reductase, plays a pivotal role in converting ribonucleotides (NTP) into deoxyribonucleotides (dNTP), essential for DNA replication and repair. Elevated RRM1 expression is associated with various human cancers, correlating with poorer prognosis and reduced overall survival rates. Our previous study found that RRM1 will enter the nucleus to promote DNA damage repair. However, the underlying mechanism remains elusive. Here, we unveil a novel role of RRM1 in promoting homologous recombination (HR) by upregulating the expression of RAD51AP1, a critical HR factor, in an E2F1-dependent manner. We demonstrate that RRM1 interacts with USP11 in the cytoplasm, and the recruitment of RRM1 to LaminB1 induced by ionizing radiation (IR) facilitates the binding of USP11 to the nuclear pore complex (NPC), promoting USP11 entry into the nucleus. Upon nuclear translocation, USP11 binds to E2F1 and inhibits the ubiquitin-mediated degradation of E2F1, thereby enhancing the transcriptional expression of RAD51AP1. Moreover, a specific RRM1 mutant lacking amino acids 731-793, crucial for its interaction with USP11 and recruitment to LaminB1, exhibits a dominant-negative effect on RAD51AP1 expression and HR. Truncations of RRM1 fail to inhibit the ubiquitin-mediated degradation of E2F1 and cannot promote the E2F1-mediated transactivation of RAD51AP1. Lastly, the full length of RRM1, not truncations, enhances tumor cells' sensitivity to IR, underscoring its importance in radiotherapy resistance. Collectively, our results suggest a novel function of RRM1 in promoting HR-mediated DSB repair through positive regulation of RAD51AP1 transcription by direct interaction with USP11 and promoting subsequent USP11-mediated deubiquitination of E2F1. Our findings elucidate a previously unknown mechanism whereby RRM1 promotes HR-mediated DNA repair, presenting a potential therapeutic target for cancer treatment.

Dataset Information

Protein disulfide isomerase blocks the interaction of LC3II-PHB2 and promotes mTOR signaling to regulate autophagy and radio/chemo-sensitivity.

Publications

Protein disulfide isomerase blocks the interaction of LC3II-PHB2 and promotes mTOR signaling to regulate autophagy and radio/chemo-sensitivity.

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