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Clinicopathological significance of endoplasmic reticulum stress proteins in ovarian carcinoma.

ABSTRACT: Epithelial ovarian cancer (EOC) is a leading cause of cancer-related mortality in the United States due to the late-stage disease at diagnosis. Overexpression of GRP78 and PDI following endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) promote growth and invasion in cancer. To identify novel prognostic biomarkers in EOC, here we determined the expression of ER stress-associated proteins (GRP78, ATF6 and PERK) and correlated with clinical outcome in EOC. Tissue microarray (TMA) samples from 415 tissues collected from three cancer centers (UM, USC, and KCCRI) were used to assess the expression levels of ER-associated proteins using immunohistochemistry (IHC). We observed that the expression levels of GRP78 (p?

SUBMITTER: Samanta S

PROVIDER: S-EPMC7005787 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Clinicopathological significance of endoplasmic reticulum stress proteins in ovarian carcinoma.

Samanta Soma S Tamura Shuzo S Dubeau Louis L Mhawech-Fauceglia Paulette P Miyagi Yohei Y Kato Hisamori H Lieberman Rich R Buckanovich Ronald J RJ Lin Yvonne G YG Neamati Nouri N

Scientific reports 20200207 1

Epithelial ovarian cancer (EOC) is a leading cause of cancer-related mortality in the United States due to the late-stage disease at diagnosis. Overexpression of GRP78 and PDI following endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) promote growth and invasion in cancer. To identify novel prognostic biomarkers in EOC, here we determined the expression of ER stress-associated proteins (GRP78, ATF6 and PERK) and correlated with clinical outcome in EOC. Tiss ...[more]

PMID: 32034256

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Project description:BackgroundMetabolic disorder is considered a well-established risk factor for endometrial carcinoma (EC). However, the mechanism remains unclear. Insulin resistance and excessive flux of free fatty acids serve as fundamental pathogenic factors in metabolic disorders, including obesity and type 2 diabetes. The aim of this study was to test the correlation between insulin resistance and dyslipidaemia in EC and to determine the effect of insulin and saturated fatty acids on EC cells.MethodsA retrospective study on the medical records of patients with EC and RNA-seq from the TCGA database analysed with edgR and Gene Ontology (GO) were used to assess the correlation of dyslipidaemia and diabetes as well as obesity. Crystal violet assays and CCK-8 assays were used to detect the proliferation of EC cells, and Annexin V-PI was used to examine apoptosis. Transient changes in mitochondrial Ca2+ and reactive oxygen species (ROS) were monitored via confocal microscopy. DNA damage was assessed by comet assays. Changes in signalling pathways were detected via phospho-kinase array. western blotting was used to assess the molecular changes in endoplasmic reticulum (ER) stress and DNA damage.ResultsWe found that glucose metabolism disorders accompanied dyslipidaemia in patients with EC. As a key regulator of glucose metabolism disorders, insulin promoted DNA damage, ROS and Ca2+ homoeostasis imbalance in a panel of established EC cell lines. Interestingly, excessive insulin boosted saturated fatty acid-induced pro-apoptotic effects in EC cells. Furthermore, our data showed that insulin synergised with saturated fatty acids to activate the mechanistic target of rapamycin kinase/70 kDa ribosomal protein S6 kinase (mTOR/p70S6K) pathway and ER stress, resulting in Ca2+ release from ER and unfolded protein response (UPR) activation, which contributed to combined insulin and saturated fatty acid treatment-induced apoptosis and tumour progression.ConclusionsOur data are the first to illustrate that impaired glucose metabolism accelerates dyslipidaemia-promoted EC progression, which is attributed to hyperinsulinaemia and saturated fatty acid-induced Ca2+ dyshomoeostasis and UPR activation in EC cells via ER stress.

Project description:BackgroundCisplatin (CDDP), a widely used chemotherapeutic agent, can induce excessive granulosa cell apoptosis, follicle loss and even premature ovarian insufficiency (POI). However, the mechanism remains elusive, although some studies have indicated the involvement of endoplasmic reticulum stress (ERS). The aim of our study was to investigate the possible mechanism ERS in CDDP-induced granulosa cell apoptosis and follicle loss.MethodsA POI mouse model was generated by CDDP. The ovaries samples were collected and processed for isobaric tags for relative and absolute quantification analysis (iTRAQ) to screen out our interested proteins of HSPA5 and HSP90AB1, and the decline in their expression were verified by a real-time quantitative PCR and a western blotting assay. In vitro, human granulosa cells, KGN and COV434 cells were transfected with siRNA targeting HSPA5 and HSP90AB1 and then treated with CDDP, or treated with CDDP with/without CDDP+?4-phenylbutyric acid (4-PBA) and 3-methyladenine (3-MA). The levels of ERS, autophagy and apoptosis were evaluated by western blotting, DALGreen staining and flow cytometry. In vivo, ovaries from mice that received intraperitoneal injections of saline, CDDP, CDDP+?4-PBA and CDDP+?3-MA were assayed by immunofluorescence, hematoxylin and eosin (H&E) staining for follicle counting, and terminal-deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) staining for cell apoptosis assay. The plasma hormone levels were measured by an enzyme-linked immunosorbent assay (ELISA) kit.ResultsWe have clarified the relationships between ERS, autophagy, and apoptosis in CDDP-induced granulosa cell apoptosis, both in vitro and in vivo. Alleviating ERS by inhibiting HSPA5 and HSP90AB1 attenuated CDDP-induced autophagy and apoptosis. 4-PBA treatment significantly attenuated CDDP-induced cell autophagy and apoptosis in cultured KGN and COV434 cells. However, inhibiting cell autophagy with 3-MA negligibly restored the CDDP-induced changes in ERS and apoptosis. In vivo experiments also demonstrated that treatment with 4-PBA, but not 3-MA, prevented CDDP-induced ovarian damage and hormone dysregulation.ConclusionsCDDP-induced ERS could promote autophagy and apoptosis in granulosa cells, causing excessive follicle loss and endocrine disorders. Alleviation of ERS with 4-PBA, but not of autophagy with 3-MA, protect against CDDP-induced granulosa cell apoptosis and ovarian damage. Thus, 4-PBA can be used to protect the ovary during chemotherapy in women.

Project description:Liver cancers, such as hepatocellular carcinoma (HCC), are a highly prevalent cause of cancer-related deaths. Current treatments to combat liver cancer are limited. (-)-Agelasidine A, a compound isolated from the methanol extract of Agelasnakamurai, a sesquiterpene guanidine derived from sea sponge, has antibacterial activity. We demonstrated its anticancer capabilities by researching the associated mechanism of (-)-agelasidine A in human liver cancer cells. We found that (-)-agelasidine A significantly reduced viability in Hep3B and HepG2 cells, and we determined that apoptosis was involved in the (-)-agelasidine A-induced Hep3B cell deaths. (-)-Agelasidine A activated caspases 9, 8, and 3, as well as PARP. This effect was reversed by caspase inhibitors, suggesting caspase-mediated apoptosis in the (-)-agelasidine A-treated Hep3B cells. Moreover, the reduced mitochondrial membrane potential (MMP) and the release of cytochrome c indicated that the (-)-agelasidine A-mediated mitochondrial apoptosis was mechanistic. (-)-Agelasidine A also increased apoptosis-associated proteins (DR4, DR5, FAS), which are related to extrinsic pathways. These events were accompanied by an increase in Bim and Bax, proteins that promote apoptosis, and a decrease in the antiapoptotic protein, Bcl-2. Furthermore, our results presented that (-)-agelasidine A treatment bridged the intrinsic and extrinsic apoptotic pathways. Western blot analysis of Hep3B cells treated with (-)-agelasidine A showed that endoplasmic reticulum (ER) stress-related proteins (GRP78, phosphorylated PERK, phosphorylated eIF2α, ATF4, truncated ATF6, and CHOP) were upregulated. Moreover, 4-PBA, an ER stress inhibitor, could also abrogate (-)-agelasidine A-induced cell viability reduction, annexin V+ apoptosis, death receptor (DR4, DR5, FAS) expression, mitochondrial dysfunction, and cytochrome c release. In conclusion, by activating ER stress, (-)-agelasidine A induced the extrinsic and intrinsic apoptotic pathways of human HCC.

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Clinicopathological significance of endoplasmic reticulum stress proteins in ovarian carcinoma.

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Clinicopathological significance of endoplasmic reticulum stress proteins in ovarian carcinoma.

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