Expression levels of MRP1, GST-π, and GSK3β in ovarian cancer and the relationship with drug resistance and prognosis of patients

Tong, Xiaojing; Zhao, Jiao; Zhang, Yuhua; Mu, Peng; Wang, Xiaobin

doi:10.3892/ol.2019.10315

Cited by 32 publications

(31 citation statements)

References 26 publications

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“…Further, microarray experiments focused on comparing the gene expression patterns between 6 sensitive and 6 resistant AsPCs to both tested drugs, and consecutive IPA network and pathway analyses, were indicative for the predominant downregulation of numerous genes and networks with previously demonstrated roles in cancer chemoresistance in the PARPis-sensitive AsPCs, as compared to the PARPis-resistant AsPCs (see Additional file 7). Most of these genes/networks (comprising calpain, STAT1, ABCB1, LGALS8, CARD10, GST, LAMB1, PBX1, AHR, IFI16, the ATPase, the MAPK and MEK networks) were shown to be related to mechanisms of EOC chemoresistance, including association with advanced EOC stage and poor prognosis [73][74][75][76][77][78][79][80][81][82][83][84][85]. Interestingly, ABCB1 induction was also shown to define a common resistance mechanism in paclitaxel-and olaparib-resistant EOC cells [74,86].…”

Section: Discussionmentioning

confidence: 99%

Development of a 3D functional assay and identification of biomarkers, predictive for response of high-grade serous ovarian cancer (HGSOC) patients to poly-ADP ribose polymerase inhibitors (PARPis): targeted therapy

et al. 2020

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Background Poly(ADP-ribose) polymerase inhibitors (PARPis) specifically target homologous recombination deficiency (HRD) cells and display good therapeutic effect in women with advanced-stage BRCA1/2-mutated breast and epithelial ovarian cancer (EOC). However, about 50% of high grade serous ovarian cancers (HGSOC) present with HRD due to epigenetic BRCA1 inactivation, as well as genetic/epigenetic inactivation(s) of other HR genes, a feature known as “BRCAness”. Therefore, there is a potential for extending the use of PARPis to these patients if HR status can be identified. Methods We have developed a 3D (spheroid) functional assay to assess the sensitivity of two PARPis (niraparib and olaparib) in ascites-derived primary cell cultures (AsPCs) from HGSOC patients. A method for AsPCs preparation was established based on a matrix (agarose), allowing for easy isolation and successive propagation of monolayer and 3D AsPCs. Based on this method, we performed cytotoxicity assays on 42 AsPCs grown both as monolayers and spheroids. Results The response to PARPis treatment in monolayer AsPCs, was significantly higher, compared to 3D AsPCs, as 88% and 52% of the monolayer AsPCs displayed sensitivity to niraparib and olaparib respectively, while 66% of the 3D AsPCs were sensitive to niraparib and 38% to olaparib, the latter being more consistent with previous estimates of HRD (40%–60%) in EOC. Moreover, niraparib displayed a significantly stronger cytotoxic effect in both in 3D and monolayer AsPCs, which was confirmed by consecutive analyses of the HR pathway activity (γH2AX foci formation) in PARPis-sensitive and resistant AsPCs. Global gene expression comparison of 6 PARPi-resistant and 6 PARPi-sensitive 3D AsPCs was indicative for the predominant downregulation of numerous genes and networks with previously demonstrated roles in EOC chemoresistance, suggesting that the PARPis-sensitive AsPCs could display enhanced sensitivity to other chemotherapeutic drugs, commonly applied in cancer management. Microarray data validation identified 24 potential gene biomarkers associated with PARPis sensitivity. The differential expression of 7 selected biomarkers was consecutively confirmed by immunohistochemistry in matched EOC tumor samples. Conclusion The application of this assay and the potential biomarkers with possible predictive significance to PARPis therapy of EOC patients now need testing in the setting of a clinical trial.

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Section: Discussionmentioning

confidence: 99%

Development of a 3D functional assay and identification of biomarkers, predictive for response of high-grade serous ovarian cancer (HGSOC) patients to poly-ADP ribose polymerase inhibitors (PARPis): targeted therapy

et al. 2020

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“…There is an urgent need for effective prognostic markers to improve OC overall survival ( Powell et al, 2005 ; Shen et al, 2017 ; Tong et al, 2019 ; Zhao et al, 2019 ). Immune cells can enhance anticancer immune responses by recognizing cancer antigens, indicating that they may influence cancer prognosis ( Drakes and Stiff, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of LncRNA Prognostic Markers for Ovarian Cancer by Integration of Co-expression and CeRNA Network

et al. 2021

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BackgroundOvarian cancer (OC), one of the most prevalent gynecological malignancies, is characterized by late detection and dismal prognosis. Recent studies show that long non-coding RNAs (lncRNAs) in competitive endogenous RNA (ceRNA) networks influence immune infiltration and cancer prognosis. However, the function of lncRNA in OC immune infiltration and prognosis remains unclear.MethodsTranscriptomes of 378 OC samples and clinical data were retrieved from the TCGA repository. Modules related to immune cells were identified using weighted gene co-expression network analysis (WGCNA). Functional enrichment analysis and survival analysis were then performed for the identification of immune-related lncRNAs in the brown module using Cox regression model. Finally, a ceRNA network was constructed by using the lncRNAs and mRNAs from the brown module.ResultsWe found lncRNAs and mRNAs in the brown module to be significantly associated with immune cells in OC and identified 4 lncRNAs as potential OC prognostic markers. We further established that lncRNAs in the ceRNA network influence OC immune infiltration and prognosis by regulating miRNA, ultimately modulating mRNA levels.ConclusionWe have identified 4 lncRNAs as independent immune prognostic factors for OC. Furthermore, our findings offer novel insight into lncRNAs as OC immune and prognostic biomarkers.

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“…Tumor cells may 2 develop resistance to alkylating anticancer drugs by increasing the levels of 2 GSTs 34 . Several subclasses in the GST family contribute to chemoresistance 2 in various cancers 15,[35][36][37][38][39][40] . GSTM1 was reported to be a predictive biomarker 2 for the efficacy of chemotherapy in breast cancer and ovarian cancer 15,35 .…”

Section: Discussionmentioning

confidence: 99%

“…CC-BY-NC-ND 4.0 International license available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprint this version posted December 14, 2020. ; https://doi.org/10.1101/2020.12.14.422655 doi: bioRxiv preprint prognosis in ovarian cancer, pancreatic ductal adenocarcinoma, and lung cancer [36][37][38][39] . As a member of the GST family, GSTZ1 plays a similar detoxification role, but it is independently characterized as a 2 maleylacetoacetate isomerase (MAAI), which is essential for phenylalanine 2 metabolism 18 .…”

Section: Discussionmentioning

confidence: 99%

GSTZ1 sensitizes hepatocellular carcinoma cells to sorafenib-induced ferroptosis via inhibition of NRF2/GPX4 axis

Wang

Cheng

Qin

et al. 2020

Preprint

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Increasing evidence supports that ferroptosis plays an important role in tumor growth inhibition. Sorafenib, originally identified as an inhibitor of multiple oncogenic kinases, has been shown to induce ferroptosis in hepatocellular carcinoma (HCC). However, some hepatoma cell lines are less sensitive to sorafenib-induced ferroptotic cell death. Glutathione S-transferase zeta 1 (GSTZ1), an enzyme in the catabolism of phenylalanine, has been found to negatively regulate the master regulator of cellular redox homeostasis nuclear factor erythroid 2-related factor 2 (NRF2). This study aimed to investigate the role of GSTZ1 in sorafenib-induced ferroptosis in HCC cell lines and determine the involved molecular mechanisms. Mechanistically, GSTZ1 depletion enhanced the activation of the NRF2 pathway and increased the glutathione peroxidase 4 (GPX4) level, thereby suppressing sorafenib-induced ferroptosis. The combination of sorafenib and RSL3, a GPX4 inhibitor, significantly inhibited GSTZ1 deficient cell viability and promoted ferroptosis, accompanied with ectopic increases of iron and lipid peroxides. An in vivo experiment showed that the combination of sorafenib and RSL3 had a synergic therapeutic effect on HCC progression in Gstz1−/− mice. In conclusion, GSTZ1 was significantly downregulated in sorafenib resistant hepatoma cells. GSTZ1 enhanced sorafenib-induced ferroptosis by inhibiting the NRF2/GPX4 axis in HCC cells. GSTZ1 deficiency was resistant to sorafenib-induced ferroptosis and is, therefore, a potential therapeutic approach for treating HCC by synergizing sorafenib and RSL3 to induce ferroptosis.

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Expression levels of MRP1, GST-π, and GSK3β in ovarian cancer and the relationship with drug resistance and prognosis of patients

Cited by 32 publications

References 26 publications

Development of a 3D functional assay and identification of biomarkers, predictive for response of high-grade serous ovarian cancer (HGSOC) patients to poly-ADP ribose polymerase inhibitors (PARPis): targeted therapy

Development of a 3D functional assay and identification of biomarkers, predictive for response of high-grade serous ovarian cancer (HGSOC) patients to poly-ADP ribose polymerase inhibitors (PARPis): targeted therapy

Identification of LncRNA Prognostic Markers for Ovarian Cancer by Integration of Co-expression and CeRNA Network

GSTZ1 sensitizes hepatocellular carcinoma cells to sorafenib-induced ferroptosis via inhibition of NRF2/GPX4 axis

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