Activation of the Unfolded Protein Response via Inhibition of Protein Disulfide Isomerase Decreases the Capacity for DNA Repair to Sensitize Glioblastoma to Radiotherapy

Liu, Yajing; Ji, Wenbin; Shergalis, Andrea; Xu, Jiaqi; Delaney, Amy M.; Calcaterra, Andrew; Pal, Anupama; Ljungman, Mats; Neamati, Nouri; Rehemtulla, Alnawaz

doi:10.1158/0008-5472.can-18-2540

Cited by 48 publications

(66 citation statements)

References 50 publications

(51 reference statements)

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“…Unfortunately, primary cultured SOD1G93A genotype neurons are not the most suitable samples to study the protective function of PDI on DNA damage, because it is impossible to artificially induce DNA damage and overexpress PDI evenly in all neurons. In the glioblastoma multiform tumor model, PDI is directly associated with DNA repair process by maintaining a specific level of DNA repair enzymes [66,67]. Thus, increasing PDI that activates the SOD1G93A protein transport into the nucleus could enhance the nucleic translocation of DNA repair enzymes by reducing ER stress.…”

Section: Discussionmentioning

confidence: 99%

Cytoplasmic Restriction of Mutated SOD1 Impairs the DNA Repair Process in Spinal Cord Neurons

Song²,

Moh³

et al. 2019

Cells

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Amyotrophic lateral sclerosis (ALS) caused by mutation of superoxide dismutase 1 (SOD1), affects various cellular processes and results in the death of motor neurons with fatal defects. Currently, several neurological disorders associated with DNA damage are known to directly induce neurodegenerative diseases. In this research, we found that cytoplasmic restriction of SOD1G93A, which inhibited the nucleic translocation of SOD1WT, was directly related to increasing DNA damage in SOD1- mutated ALS disease. Our study showed that nucleic transport of DNA repair- processing proteins, such as p53, APEX1, HDAC1, and ALS- linked FUS were interfered with under increased endoplasmic reticulum (ER) stress in the presence of SOD1G93A. During aging, the unsuccessful recognition and repair process of damaged DNA, due to the mislocalized DNA repair proteins might be closely associated with the enhanced susceptibility of DNA damage in SOD1- mutated neurons. In addition, the co-expression of protein disulphide isomerase (PDI) directly interacting with SOD1 protein in neurons enhances the nucleic transport of cytoplasmic- restricted SOD1G93A. Therefore, our results showed that enhanced DNA damage by SOD1 mutation-induced ALS disease and further suggested that PDI could be a strong candidate molecule to protect neuronal apoptosis by reducing DNA damage in ALS disease.

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Section: Discussionmentioning

confidence: 99%

Cytoplasmic Restriction of Mutated SOD1 Impairs the DNA Repair Process in Spinal Cord Neurons

Song²,

Moh³

et al. 2019

Cells

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“…To meet this demand, upregulation of proteins such as protein disulfide isomerases (PDI) is usually observed. 9 The PDI family is a group of enzymes in the ER responsible for the formation, breakdown and rearrangement of protein disulfide bonds, consisting of 21 members. Among the PDI family, PDIA6 is overexpressed in BC tissues and cell lines, and PDIA3 is helpful for predicting the prognosis of BC.…”

Section: Introductionmentioning

confidence: 99%

<p>Targeted Inhibition of P4HB Promotes Cell Sensitivity to Gemcitabine in Urothelial Carcinoma of the Bladder</p>

Wang¹,

Bai²,

Yang³

et al. 2020

OTT

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Background: Bladder cancer (BC) is a common malignancy worldwide that accounts for 3% of global cancer diagnoses. Chemotherapy resistance limits the therapeutic effect of chemotherapeutic agents in patients with BC. Prolyl 4-hydroxylase, beta polypeptide (P4HB) is an endoplasmic reticulum (ER) chaperone that is upregulated in bladder cancer tissues (The Cancer Genome Atlas, TCGA datasets). Knockdown or suppression of P4HB exerts anticancer activity and sensitizes cells to chemotherapy in various types of cancer. Purpose: We aimed to investigate whether the inhibition of P4HB enhances the anticancer efficacy of gemcitabine (GEM) in BC cells and to study the underlying molecular mechanisms. Patients and Methods: The P4HB mRNA expression levels of 411 BC patients from the TCGA database and P4HB expression level of eighty BC paraffin-embedded samples detected by immunohistochemistry (IHC) staining were used for clinical feature and prognostic analyses. Bioinformatics analysis was utilized for the mechanistic investigation. Highly P4HB-expressed BC cell lines (T24 and 5637) treated with P4HB inhibitor (Bacitracin, BAC) were used to study the effects of BAC on the sensitivity of BC cells to GEM and the potential mechanism. P4HB inhibition experiments were performed in highly P4HB-expressed BC cells, and cell viability, colony formation, cell cycle, reactive oxygen species (ROS), apoptosis and pathway proteins were assessed in T24 and 5637 cells. Results: Western blot analysis showed that P4HB expression was significantly higher in BC tissues than in paired normal tissues. IHC showed that patients with high P4HB expression had a poorer overall survival (OS) rate than those with low P4HB expression. Furthermore, increased P4HB expression was demonstrated to be an independent prognostic marker for BC. Functionally, P4HB inhibition by BAC decreased the cell proliferation ability in vitro. Moreover, BAC treatment sensitized BC cells to GEM. Molecular mechanism analysis indicated that inhibition of P4HB by BAC treatment enhanced the anticancer effects of GEM through increasing cellular ROS content and promoting cell apoptosis and PERK/eIF2α/ATF4/CHOP signaling. Conclusion: High P4HB expression was significantly correlated with poor prognosis in BC patients. Inhibition of P4HB by BAC decreased the cell proliferation ability and sensitized BC cells to GEM by activating apoptosis and the PERK/eIF2α/ATF4/CHOP pathways.

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“…The latter result would also explain why CITK knockdown is by itself capable of inducing genomic instability [16,31]. CITK may directly impair RAD51 nuclear-cytoplasmic shuttling or nuclear RAD51 stability [38,[49][50][51]. These mechanisms would be consistent with the fact that CITK is capable of forming a physical complex with RAD51, especially when CITK catalytic activity is compromised [16].…”

Section: Discussionmentioning

confidence: 70%

“…The finding of reduced total levels of this protein suggests that DSB accumulation detected in MB cells could be caused by reduced efficiency of HR-dependent repair pathway. Since RAD51 operates in the nuclear compartment and its loss induces DNA damage and radiosensitization [38], we set out to evaluate nuclear RAD51 levels in CITK-depleted MB cells. To this aim, we resorted to ONS-76 and DAOY, which we previously engineered for conditionally expressing CITK-specific shRNAs [31].…”

Section: Citk Knockdown Strongly Reduces Nuclear Rad51 Levels In Mb Cmentioning

confidence: 99%

CITK Loss Inhibits Growth of Group 3 and Group 4 Medulloblastoma Cells and Sensitizes Them to DNA-Damaging Agents

Pallavicini

Iegiani

Berto

et al. 2020

Cancers

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Medulloblastoma (MB) is the most common malignant brain tumor in children, and it is classified into four biological subgroups: WNT, Sonic Hedgehog (SHH), Group 3 and Group 4. The current treatment is surgery, followed by irradiation and chemotherapy. Unfortunately, these therapies are only partially effective. Citron kinase protein (CITK) has been proposed as a promising target for SHH MB, whose inactivation leads to DNA damage and apoptosis. D283 and D341 cell lines (Group 3/Group 4 MB) were silenced with established siRNA sequences against CITK, to assess the direct effects of its loss. Next, D283, D341, ONS-76 and DAOY cells were treated with ionizing radiation (IR) or cisplatin in combination with CITK knockdown. CITK depletion impaired proliferation and induced cytokinesis failure and apoptosis of G3/G4 MB cell lines. Furthermore, CITK knockdown produced an accumulation of DNA damage, with reduced RAD51 nuclear levels. Association of IR or cisplatin with CITK depletion strongly impaired the growth potential of all tested MB cells. These results indicate that CITK inactivation could prevent the expansion of G3/G4 MB and increase their sensitivity to DNA-damaging agents, by impairing homologous recombination. We suggest that CITK inhibition could be broadly associated with IR and adjuvant therapy in MB treatment.

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Activation of the Unfolded Protein Response via Inhibition of Protein Disulfide Isomerase Decreases the Capacity for DNA Repair to Sensitize Glioblastoma to Radiotherapy

Abstract: ER stress Proteasome Degraded RAD51 Ionizing radiation Accumulation of DNA damage & cell death

Cited by 48 publications

References 50 publications

Cytoplasmic Restriction of Mutated SOD1 Impairs the DNA Repair Process in Spinal Cord Neurons

Cytoplasmic Restriction of Mutated SOD1 Impairs the DNA Repair Process in Spinal Cord Neurons

<p>Targeted Inhibition of P4HB Promotes Cell Sensitivity to Gemcitabine in Urothelial Carcinoma of the Bladder</p>

CITK Loss Inhibits Growth of Group 3 and Group 4 Medulloblastoma Cells and Sensitizes Them to DNA-Damaging Agents

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