Highly cytotoxic gold(i)-phosphane dithiocarbamate complexes trigger an ER stress-dependent immune response in ovarian cancer cells

2020 ◽  
Vol 49 (22) ◽  
pp. 7355-7363 ◽  
Author(s):  
Hai Van Le ◽  
Maria V. Babak ◽  
Muhammad Ali Ehsan ◽  
Muhammad Altaf ◽  
Lisa Reichert ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Immune Response ◽  
Immune System ◽  
Er Stress ◽  
Cancer Cells ◽  
Ovarian Cancer Cells ◽  
System P ◽  
Stress Dependent

Highly cytotoxic AuI-dithiocarbamate complexes were designed to induce severe integrative stress in ovarian cancer cells, leading to the surface exposure of calreticulin, which is a first step in the activation of immune system.

scholarly journals A Combination of Glutaminase Inhibitor 968 and PD-L1 Blockade Boosts the Immune Response against Ovarian Cancer

Biomolecules ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1749
Author(s):  
Jing-Jing Wang ◽  
Michelle Kwan-Yee Siu ◽  
Yu-Xin Jiang ◽  
Thomas Ho-Yin Leung ◽  
David Wai Chan ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Immune Response ◽  
T Cells ◽  
Cancer Cells ◽  
Cd8 T Cells ◽  
Granzyme B ◽  
Combined Treatment ◽  
In Vivo Studies ◽  
Immune Checkpoints ◽  
Ovarian Cancer Cells

Programmed cell death 1 ligand (PD-L1) blockade has been used therapeutically in the treatment of ovarian cancer, and potential combination treatment approaches are under investigation to improve the treatment response rate. The increased dependence on glutamine is widely observed in various type of tumors, including ovarian cancer. Kidney-type glutaminase (GLS), as one of the isotypes of glutaminase, is found to promote tumorigenesis. Here, we have demonstrated that the combined treatment with GLS inhibitor 968 and PD-L1 blockade enhances the immune response against ovarian cancer. Survival analysis using the Kaplan–Meier plotter dataset from ovarian cancer patients revealed that the expression level of GLS predicts poor survival and correlates with the immunosuppressive microenvironment of ovarian cancer. 968 inhibits the proliferation of ovarian cancer cells and enhances granzyme B secretion by CD8+ T cells as detected by XTT assay and flow cytometry, respectively. Furthermore, 968 enhances the apoptosis-inducing ability of CD8+ T cells toward cancer cells and improves the treatment effect of anti-PD-L1 in treating ovarian cancer as assessed by Annexin V apoptosis assay. In vivo studies demonstrated the prolonged overall survival upon combined treatment of 968 with anti-PD-L1 accompanied by increased granzyme B secretion by CD4+ and CD8+ T cells isolated from ovarian tumor xenografts. Additionally, 968 increases the infiltration of CD3+ T cells into tumors, possibly through enhancing the secretion of CXCL10 and CXCL11 by tumor cells. In conclusion, our findings provide a novel insight into ovarian cancer cells influence the immune system in the tumor microenvironment and highlight the potential clinical implication of combination of immune checkpoints with GLS inhibitor 968 in treating ovarian cancer.

scholarly journals PD-L1 regulates tumorigenesis and autophagy of ovarian cancer by activating mTORC signaling

2019 ◽  
Vol 39 (12) ◽  
Author(s):  
Hongmin Gao ◽  
Juan Zhang ◽  
Xiaohong Ren
Keyword(s):  
Ovarian Cancer ◽  
Immune Response ◽  
Cancer Cells ◽  
Clinical Significance ◽  
Tumour Cell ◽  
Normal Tissue ◽  
Ovarian Tumour ◽  
Ovarian Cancer Cells ◽  
Adjacent Normal Tissue ◽  
Novel Strategy

Abstract PD-L1 is a well-known immune co-stimulatory molecule that regulates tumour cell escape from immunity by suppressing the immune response. However, the clinical significance of PD-L1 in the progression of ovarian cancer is unclear. Our study demonstrated that PD-L1 is up-regulated in ovarian tumour tissue compared with its expression level in adjacent normal tissue. Furthermore, we confirmed that PD-L1 increases the proliferation of cancer cells by activating the AKT-mTORC signalling pathway, which is also enhanced by the expression of S6K, the substrate of mTORC. In addition, PD-L1 promotes the autophagy of ovarian cancer cells by up-regulating the expression of BECN1, a crucial molecule involved in the regulation of autophagy. In conclusion, PD-L1 may provide a target for the development of a novel strategy for the treatment of ovarian cancer.

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

scholarly journals Photodynamic Therapy Using a New Folate Receptor-Targeted Photosensitizer on Peritoneal Ovarian Cancer Cells Induces the Release of Extracellular Vesicles with Immunoactivating Properties

2020 ◽  
Vol 9 (4) ◽  
pp. 1185 ◽  
Author(s):  
Martha Baydoun ◽  
Olivier Moralès ◽  
Céline Frochot ◽  
Colombeau Ludovic ◽  
Bertrand Leroux ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Immune Response ◽  
Photodynamic Therapy ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Extracellular Vesicles ◽  
Immune Cells ◽  
Surgical Techniques ◽  
Ovarian Cancer Cells ◽  
The Impact

Often discovered at an advanced stage, ovarian cancer progresses to peritoneal carcinoma, which corresponds to the invasion of the serosa by multiple tumor implants. The current treatment is based on the combination of chemotherapy and tumor cytoreduction surgery. Despite the progress and standardization of surgical techniques combined with effective chemotherapy, post-treatment recurrences affect more than 60% of women in remission. Photodynamic therapy (PDT) has been particularly indicated for the treatment of superficial lesions on large surfaces and appears to be a relevant candidate for the treatment of microscopic intraperitoneal lesions and non-visible lesions. However, the impact of this therapy on immune cells remains unclear. Hence, the objective of this study is to validate the efficacy of a new photosensitizer [pyropheophorbide a-polyethylene glycol-folic acid (PS)] on human ovarian cancer cells and to assess the impact of the secretome of PDT-treated cells on human peripheral blood mononuclear cells (PBMC). We show that PS, upon illumination, can induce cell death of different ovarian tumor cells. Furthermore, PDT using this new PS seems to favor activation of the immune response by inducing the secretion of effective cytokines and inhibiting the pro-inflammatory and immunosuppressive ones, as well as releasing extracellular vesicles (EVs) prone to activating immune cells. Finally, we show that PDT can activate CD4+ and CD8+ T cells, resulting in a potential immunostimulating process. The results of this pilot study therefore indicate that PS-PDT treatment may not only be effective in rapidly and directly destroying target tumor cells but also promote the activation of an effective immune response; notably, by EVs. These data thus open up good prospects for the treatment of micrometastases of intraperitoneal ovarian carcinosis which are currently inoperable.

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 Deciphering the Molecular Mechanism of Spontaneous Senescence in Primary Epithelial Ovarian Cancer Cells

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 296 ◽  
Author(s):  
Martyna Pakuła ◽  
Ewa Mały ◽  
Paweł Uruski ◽  
Anna Witucka ◽  
Małgorzata Bogucka ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Cancer Cells ◽  
Malignant Ascites ◽  
Cyclin B1 ◽  
Ovarian Cancer Cells ◽  
Independent Manner ◽  
Primary Epithelial Ovarian Cancer ◽  
Stress Dependent

Spontaneous senescence of cancer cells remains a puzzling and poorly understood phenomenon. Here we comprehensively characterize this process in primary epithelial ovarian cancer cells (pEOCs). Analysis of tumors from ovarian cancer patients showed an abundance of senescent cells in vivo. Further, serially passaged pEOCs become senescent after a few divisions. These senescent cultures display trace proliferation, high expression of senescence biomarkers (SA-β-Gal, γ-H2A.X), growth-arrest in the G1 phase, increased level of cyclins D1, D2, decreased cyclin B1, up-regulated p16, p21, and p53 proteins, eroded telomeres, reduced activity of telomerase, predominantly non-telomeric DNA damage, activated AKT, AP-1, and ERK1/2 signaling, diminished JNK, NF-κB, and STAT3 pathways, increased formation of reactive oxygen species, unchanged activity of antioxidants, increased oxidative damage to DNA and proteins, and dysfunctional mitochondria. Moreover, pEOC senescence is inducible by normal peritoneal mesothelium, fibroblasts, and malignant ascites via the paracrine activity of GRO-1, HGF, and TGF-β1. Collectively, pEOCs undergo spontaneous senescence in a mosaic, telomere-dependent and telomere-independent manner, plausibly in an oxidative stress-dependent mechanism. The process may also be activated by extracellular stimuli. The biological and clinical significance of pEOC senescence remains to be explored.

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
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