scholarly journals Targeting the IRE1α/XBP1s pathway suppresses CARM1-expressing ovarian cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jianhuang Lin ◽  
Heng Liu ◽  
Takeshi Fukumoto ◽  
Joseph Zundell ◽  
Qingqing Yan ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Stress Response ◽  
Er Stress ◽  
Cancer Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Ovarian Cancer Cells ◽  
Dependent Manner ◽  
Er Stress Response

AbstractCARM1 is often overexpressed in human cancers including in ovarian cancer. However, therapeutic approaches based on CARM1 expression remain to be an unmet need. Cancer cells exploit adaptive responses such as the endoplasmic reticulum (ER) stress response for their survival through activating pathways such as the IRE1α/XBP1s pathway. Here, we report that CARM1-expressing ovarian cancer cells are selectively sensitive to inhibition of the IRE1α/XBP1s pathway. CARM1 regulates XBP1s target gene expression and directly interacts with XBP1s during ER stress response. Inhibition of the IRE1α/XBP1s pathway was effective against ovarian cancer in a CARM1-dependent manner both in vitro and in vivo in orthotopic and patient-derived xenograft models. In addition, IRE1α inhibitor B-I09 synergizes with immune checkpoint blockade anti-PD1 antibody in an immunocompetent CARM1-expressing ovarian cancer model. Our data show that pharmacological inhibition of the IRE1α/XBP1s pathway alone or in combination with immune checkpoint blockade represents a therapeutic strategy for CARM1-expressing cancers.

scholarly journals WWOX sensitises ovarian cancer cells to paclitaxel via modulation of the ER stress response

2017 ◽  
Vol 8 (7) ◽  
pp. e2955-e2955 ◽  
Author(s):  
Szymon Janczar ◽  
Jaya Nautiyal ◽  
Yi Xiao ◽  
Edward Curry ◽  
Mingjun Sun ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Stress Response ◽  
Er Stress ◽  
Cancer Cells ◽  
Ovarian Cancer Cells ◽  
Er Stress Response

scholarly journals Propofol suppresses cell viability, cell cycle progression and motility and induces cell apoptosis of ovarian cancer cells through suppressing MEK/ERK signaling via targeting circVPS13C/miR-145 axis

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Huan Lu ◽  
Guanlin Zheng ◽  
Xiang Gao ◽  
Chanjuan Chen ◽  
Min Zhou ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Ovarian Cancer ◽  
Cancer Cells ◽  
Rna Binding ◽  
Erk Signaling ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Ovarian Cancer Cells ◽  
Dependent Manner ◽  
Vacuolar Protein

Abstract Background Propofol is a kind of common intravenous anaesthetic agent that plays an anti-tumor role in a variety of cancers, including ovarian cancer. However, the working mechanism of Propofol in ovarian cancer needs further exploration. Methods The viability and metastasis of ovarian cancer cells were assessed by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and transwell assays. Flow cytometry was used to evaluate the cell cycle and apoptosis. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to examine the abundance of circular RNA vacuolar protein sorting 13 homolog C (circVPS13C) and microRNA-145 (miR-145). The target relationship between miR-145 and circVPS13C was predicted by circinteractome database and verified by dual-luciferase reporter assay, RNA-binding protein immunoprecipitation (RIP) assay and RNA-pull down assay. Western blot assay was used to detect the levels of phosphorylated extracellular regulated MAP kinase (p-ERK), ERK, p-MAP kinse-ERK kinase (p-MEK) and MEK, in ovarian cancer cells. Results Propofol treatment suppressed the viability, cell cycle and motility and elevated the apoptosis rate of ovarian cancer cells. Propofol up-regulated miR-145 in a dose-dependent manner. Propofol exerted an anti-tumor role partly through up-regulating miR-145. MiR-145 was a direct target of circVPS13C. Propofol suppressed the progression of ovarian cancer through up-regulating miR-145 via suppressing circVPS13C. Propofol functioned through circVPS13C/miR-145/MEK/ERK signaling in ovarian cancer cells. Conclusion Propofol suppressed the proliferation, cell cycle, migration and invasion and induced the apoptosis of ovarian cancer cells through circVPS13C/miR-145/MEK/ERK signaling in vitro.

scholarly journals Immune checkpoint blockade in ovarian cancer

2016 ◽  
Vol 9 (2) ◽  
pp. 82-84 ◽  
Author(s):  
Lukas Weiss ◽  
Florian Huemer ◽  
Brigitte Mlineritsch ◽  
Richard Greil
Keyword(s):  
Ovarian Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade

scholarly journals 700 Increasing MHC-I expression to potentiate immune checkpoint blockade therapy

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A728-A728
Author(s):  
Shengqing Gu ◽  
Wubing Zhang ◽  
Xiaoqing Wang ◽  
Peng Jiang ◽  
Nicole Traugh ◽  
...  
Keyword(s):  
T Cell ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Mhc I ◽  
Expression Signature ◽  
Smac Mimetics ◽  
Smac Mimetic

BackgroundCancer immunotherapy, especially immune checkpoint blockade (ICB) therapy, is leading to a paradigm shift in cancer treatment, as a small percentage of cancer patients have obtained durable remission following ICB treatment. Successful ICB responses rely on cancer cells presenting antigens to the cell surface via the major histocompatibility complex (MHC), which activates antigen-specific T-lymphocytes to kill cancer cells. Type-I MHC (MHC-I) is wildly expressed in all cell types and mediates the interaction with cytotoxic CD8 T cells. However, over 65% of cancer patients are estimated to show defects in MHC-I-mediated antigen presentation, including downregulation of its expression that can lead to primary or acquired resistance to ICB therapy, and therapeutic strategies to effectively restore or boost MHC-I are limited.MethodsHere, we employed a CRISPR screening approach with dual-marker FACS sorting to identify factors that decouple the regulation of MHC-I and PD-L1. The experimentally validated target was used to generate a KO differential expression signature. Using this signature, we analyzed transcriptome data from drug perturbation studies to identify drugs that regulate MHC-I but not PD-L1. Finally, we validated the effect of the identified drug to enhance ICB response in a T-cell-dependent manner in vivo.ResultsCRISPR screens identified TRAF3, a suppressor of the NF-κB pathway, as a negative regulator of MHC-I but not PD-L1. The Traf3-knockout (Traf3-KO) gene expression signature is associated with better survival in ICB-naive cancer patients and better ICB response. We then screened for drugs with similar transcriptional effects as this signature and identified SMAC mimetics. We experimentally validated that the SMAC mimetic birinapant upregulates MHC-I, sensitizes cancer cells to T-cell-dependent killing, and adds to ICB efficacy. However, in cancer cells with high NF-κB activity, the effect of birinapant on MHC-I is weak, indicating context-dependent MHC-I regulation.ConclusionsIn summary, Traf3 deletion specifically upregulates MHC-I without inducing PD-L1 in response to various cytokines and sensitizes cancer cells to T-cell-driven cytotoxicity. The SMAC mimetic birinapant phenocopies Traf3-knockout and sensitizes MHC-I-low melanoma to ICB therapy. Further studies are needed to elucidate the context-dependencies of MHC-I regulation. Our findings provide preclinical rationale for treating some tumors expressing low MHC-I with SMAC mimetics to enhance sensitivity to immunotherapy. The approach used in this study can be generalized to identify other drugs that enhance immunotherapy efficacy.AcknowledgementsThis study was supported by grants from the NIH (R01CA234018 to XSL, R01AI137337 to BEG, P50CA101942-12 and P50CA206963 to GJF), Breast Cancer Research Foundation (BCRF-19-100 to XSL), Burroughs Wellcome Career Award in Medical Sciences (to BEG), and Sara Elizabeth O'Brien Trust Fellowship (to SG).We thank Drs. Kai Wucherpfennig and Deng Pan for their insightful suggestions on this study.Ethics ApprovalAll mice were housed in standard cage in Dana-Farber Cancer Institute Animal Resources Facility (ARF). All animal procedures were carried out under the ARF Institutional Animal Care and Use Committee (IACUC) protocol and were in accordance with the IACUC standards for the welfare of animals.

scholarly journals Constitutive Photomorphogenic 1 Enhances ER Stress Tolerance in Arabidopsis

2021 ◽  
Vol 22 (19) ◽  
pp. 10772
Author(s):  
Chang Ho Kang ◽  
Eun Seon Lee ◽  
Ganesh M. Nawkar ◽  
Joung Hun Park ◽  
Seong Dong Wi ◽  
...  
Keyword(s):  
Stress Response ◽  
Er Stress ◽  
Stress Conditions ◽  
Negative Regulator ◽  
Light Signaling ◽  
Dependent Manner ◽  
Wild Type ◽  
Er Stress Response ◽  
The Unfolded Protein Response ◽  
Mutant Locus

Interaction between light signaling and stress response has been recently reported in plants. Here, we investigated the role of CONSTITUTIVE PHOTOMORPHOGENIC 1 (COP1), a key regulator of light signaling, in endoplasmic reticulum (ER) stress response in Arabidopsis. The cop1-4 mutant Arabidopsis plants were highly sensitive to ER stress induced by treatment with tunicarmycin (Tm). Interestingly, the abundance of nuclear-localized COP1 increased under ER stress conditions. Complementation of cop1-4 mutant plants with the wild-type or variant types of COP1 revealed that the nuclear localization and dimerization of COP1 are essential for its function in plant ER stress response. Moreover, the protein amount of ELONGATED HYPOCOTYL 5 (HY5), which inhibits bZIP28 to activate the unfolded protein response (UPR), decreased under ER stress conditions in a COP1-dependent manner. Accordingly, the binding of bZIP28 to the BIP3 promoter was reduced in cop1-4 plants and increased in hy5 plants compared with the wild type. Furthermore, introduction of the hy5 mutant locus into the cop1-4 mutant background rescued its ER stress-sensitive phenotype. Altogether, our results suggest that COP1, a negative regulator of light signaling, positively controls ER stress response by partially degrading HY5 in the nucleus.

Trichomonas Vaginalis Induces Apoptosis via ROS and ER Stress Through ER-mitochondria Crosstalk in Human Cervical Epithelial Cells

2021 ◽  
Author(s):  
Fei Fei Gao ◽  
Juan-Hua Quan ◽  
Min A Lee ◽  
Wei Ye ◽  
Jae-Min Yuk ◽  
...  
Keyword(s):  
Stress Response ◽  
Epithelial Cells ◽  
Er Stress ◽  
Mitochondrial Dysfunction ◽  
Parasite Burden ◽  
Dependent Manner ◽  
Ros Production ◽  
Er Stress Response ◽  
Siha Cells ◽  
Mitochondrial Ros

Abstract Background: Human trichomoniasis is one of the most common sexually transmitted infections; however, its pathogenesis remains unclear. Here, we investigated the role of the endoplasmic reticulum (ER) in apoptosis induction by T. vaginalis in human cervical epithelial SiHa cellsMethods: We evaluated the cytotoxicity, apoptosis, reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP), ER stress response, and Bcl-2 family protein expressions using LDH assay, immunocytochemistry, flow cytometry, JC-1 dye staining, and western blotting.Results: T. vaginalis induced LDH-dependent cytotoxicity, mitochondrial ROS production, and apoptosis in SiHa cells, parasite burden- and infection time-dependently. T. vaginalis also induced ER stress response and mitochondrial dysfunction, such as MMP depolarization and imbalance in levels of Bcl-2 family proteins, in SiHa cells in a parasite burden- and infection time-dependent manner. Pretreatment with N-Acetyl cysteine (ROS scavenger) or 4-phenylbutyric acid (4-PBA, ER stress inhibitor) significantly alleviated apoptosis, ROS production, mitochondrial dysfunction, and ER stress response in a dose-dependent manner. These data suggested that SiHa cell apoptosis is affected by ROS and ER stress after T. gondii infection. In addition, T. vaginalis induced ASK1 and JNK phosphorylation in SiHa cells, however 4-PBA or SP600125 (JNK inhibitor) pretreatment significantly attenuated ASK1/JNK phosphorylation, mitochondrial dysfunction, apoptosis, and ER stress response in SiHa cells, dose-dependently.Conclusions: T. vaginalis induces mitochondrial apoptosis via ROS and parasite-mediated ER stress via the IRE1/ASK1/JNK/Mcl-1 pathways, and also induces ER stress response directly and mitochondrial ROS-dependently in human cervical epithelial SiHa cells, thus, T. vaginalis induces apoptosis via ROS and ER stress through ER-mitochondria crosstalk in human cervical epithelial cells. These results expand our understanding of the molecular mechanisms underlying the pathogenesis of human trichomoniasis.

scholarly journals Trans10,cis12 conjugated linoleic acid inhibits proliferation and migration of ovarian cancer cells by inducing ER stress, autophagy, and modulation of Src

PLoS ONE ◽  
2018 ◽  
Vol 13 (1) ◽  
pp. e0189524 ◽  
Author(s):  
Mian M. K. Shahzad ◽  
Mildred Felder ◽  
Kai Ludwig ◽  
Hannah R. Van Galder ◽  
Matthew L. Anderson ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Linoleic Acid ◽  
Er Stress ◽  
Cancer Cells ◽  
Conjugated Linoleic Acid ◽  
Ovarian Cancer Cells ◽  
And Migration ◽  
Proliferation And Migration
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