Chemoresistant Cancer Cell Lines Are Characterized by Migratory, Amino Acid Metabolism, Protein Catabolism and IFN1 Signalling Perturbations

Acland, Mitchell; Lokman, Noor A.; Young, Clifford; Anderson, Dovile; Condina, Mark R.; Desire, Chris; Noye, Tannith M.; Wang, Wanqi; Ricciardelli, Carmela; Creek, Darren J.; Oehler, Martin K.; Hoffmann, Peter; Klingler‐Hoffmann, Manuela

doi:10.3390/cancers14112763

Cited by 6 publications

(8 citation statements)

References 96 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, the positive expression profiling of TGFBI with important ECM remodeling proteins such as GFPT2, FLNA, G6PD, ITGAV, ITGA1 and ITGA2 shown by TIMER datasets suggest a potential role of these proteins in remodeling ECM in response to carboplatin treatment. Consistent with our findings, a recent study has shown increased migratory, amino acid metabolism, protein catabolism and IFN1 signaling perturbation in platinum resistant ovarian cancer cell lines [ 60 ].…”

Section: Discussionsupporting

confidence: 93%

Platinum-resistance in epithelial ovarian cancer: an interplay of epithelial–mesenchymal transition interlinked with reprogrammed metabolism

Leung¹,

Price

Lokman

et al. 2022

J Transl Med

Self Cite

View full text Add to dashboard Cite

Background Epithelial ovarian cancer is the most lethal gynaecological cancer worldwide. Chemotherapy resistance represents a significant clinical challenge and is the main reason for poor ovarian cancer prognosis. We identified novel expression of markers related to epithelial mesenchymal transitions (EMT) in a carboplatin resistant ovarian cancer cell line by proteomics. This was validated in the platinum resistant versus sensitive parental cell lines, as well as platinum resistant versus sensitive human ovarian cancer patient samples. The prognostic significance of the different proteomics-identified marker proteins in prognosis prediction on survival as well as their correlative association and influence on immune cell infiltration was determined by public domain data bases. Methods We explored the proteomic differences between carboplatin-sensitive OVCAR5 cells (parental) and their carboplatin-resistant counterpart, OVCAR5 CBPR cells. qPCR and western blots were performed to validate differentially expressed proteins at the mRNA and protein levels, respectively. Association of the identified proteins with epithelial–mesenchymal transition (EMT) prompted the investigation of cell motility. Cellular bioenergetics and proliferation were studied to delineate any biological adaptations that facilitate cancer progression. Expression of differentially expressed proteins was assessed in ovarian tumors obtained from platinum-sensitive (n = 15) versus platinum-resistant patients (n = 10), as well as matching tumors from patients at initial diagnosis and following relapse (n = 4). Kaplan–Meier plotter and Tumor Immune Estimation Resource (TIMER) databases were used to determine the prognostic significance and influence of the different proteomics-identified proteins on immune cell infiltration in the tumor microenvironment (TME). Results Our proteomics study identified 2422 proteins in both cell lines. Of these, 18 proteins were upregulated and 14 were downregulated by ≥ twofold (p < 0.05) in OVCAR5 CBPR cells. Gene ontology enrichment analysis amongst upregulated proteins revealed an overrepresentation of biological processes consistent with EMT in the resistant cell line. Enhanced mRNA and/or protein expression of the identified EMT modulators including ITGA2, TGFBI, AKR1B1, ITGAV, ITGA1, GFPT2, FLNA and G6PD were confirmed in OVCAR5 CBPR cells compared to parental OVCAR5 cell line. Consistent with the altered EMT profile, the OVCAR5 CBPR cells demonstrated enhanced migration and reduced proliferation, glycolysis, and oxidative phosphorylation. The upregulation of G6PD, AKR1B1, ITGAV, and TGFβ1 in OVCAR5 CBPR cells was also identified in the tumors of platinum-resistant compared to platinum-sensitive high grade serous ovarian cancer (HGSOC) patients. Matching tumors of relapsed versus newly diagnosed HGSOC patients also showed enhanced expression of AKR1B1, ITGAV, TGFβ1 and G6PD protein in relapsed tumors. Among the identified proteins, significant enhanced expression of GFPT2, FLNA, TGFBI (CDGG1), ITGA2 predicted unfavorable prognosis in ovarian cancer patients. Further analysis suggested that the expression of TGFBI to correlate positively with the expression of identified and validated proteins such as GFPT2, FLNA, G6PD, ITGAV, ITGA1 and ITGA2; and with the infiltration of CD8+ T cells, macrophages, neutrophils, and dendritic cells in the TME. Conclusions Our research demonstrates proteomic-based discovery of novel EMT-related markers with an altered metabolic profile in platinum-resistant versus sensitive ovarian cancer cell lines. The study also confirms the expression of selected identified markers in the tumors of platinum-resistant versus sensitive, and in matching relapsed versus newly diagnosed HGSOC patients. The study provides insights into the metabolic adaptation of EMT-induced carboplatin resistant cells that confers on them reduced proliferation to provide effective migratory advantage; and the role of some of these identified proteins in ovarian cancer prognosis. These observations warrant further investigation of these novel target proteins in platinum-resistant patients.

show abstract

Section: Discussionsupporting

confidence: 93%

Platinum-resistance in epithelial ovarian cancer: an interplay of epithelial–mesenchymal transition interlinked with reprogrammed metabolism

Leung¹,

Price

Lokman

et al. 2022

J Transl Med

Self Cite

View full text Add to dashboard Cite

show abstract

“…OVCAR-5, the human ovarian cancer cell line, was obtained from Dr. Thomas Hamilton (Fox Chase Cancer Centre, Philadelphia, PA) and cultured under similar conditions to those previously described by us [ 17 , 22 ]. Briefly, the carboplatin-resistant (CBPR) OVCAR-5 cells were obtained by treating parental OVCAR-5 cells with 25 µM of carboplatin for 24 h. (Hospira Australia Pty Ltd., Mulgrave, Australia) followed by 72 h of recovery phase.…”

Section: Methodsmentioning

confidence: 99%

“…Recently we have generated carboplatin-resistant cancer cell lines (OVCAR-5 and CaOV3). Label-free proteomics analysis on these two pairs of parental and carboplatin-resistant cell lines showed a shared dysregulation of cytokine and type 1 interferon signaling, potentially revealing a common molecular feature of chemoresistance [ 17 ]. Here, we aimed to identify protein markers of chemotherapy response in HGSOC patients who did not respond to platinum-based chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, Kaplan–Meier analysis revealed elevated levels of GSN and TXN mRNA expression correlated with increased overall survival (OS) and progression-free survival (PFS), respectively. The relative expression of the proteins was further confirmed by DIA LC–MS in the ovarian cancer cell line OVCAR-5, where parental cells were compared to cells that had been treated with carboplatin to develop acquired chemoresistance [ 17 ]. The differential expression of GSN, CALM1, and TXN in the parental OVCAR-5 cells compared to carboplatin-resistant (CBPR) OVCAR-5 cells showed similar expression, as observed in the patient cohort.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Label-Free Quantification Mass Spectrometry Identifies Protein Markers of Chemotherapy Response in High-Grade Serous Ovarian Cancer

Arentz

Mittal

Klingler‐Hoffmann

et al. 2023

Cancers

Self Cite

View full text Add to dashboard Cite

Eighty percent of ovarian cancer patients initially respond to chemotherapy, but the majority eventually experience a relapse and die from the disease with acquired chemoresistance. In addition, 20% of patients do not respond to treatment at all, as their disease is intrinsically chemotherapy resistant. Data-independent acquisition nano-flow liquid chromatography–mass spectrometry (DIA LC-MS) identified the three protein markers: gelsolin (GSN), calmodulin (CALM1), and thioredoxin (TXN), to be elevated in high-grade serous ovarian cancer (HGSOC) tissues from patients that responded to chemotherapy compared to those who did not; the differential expression of the three protein markers was confirmed by immunohistochemistry. Analysis of the online GENT2 database showed that mRNA levels of GSN, CALM1, and TXN were decreased in HGSOC compared to fallopian tube epithelium. Elevated levels of GSN and TXN mRNA expression correlated with increased overall and progression-free survival, respectively, in a Kaplan–Meier analysis of a large online repository of HGSOC patient data. Importantly, differential expression of the three protein markers was further confirmed when comparing parental OVCAR-5 cells to carboplatin-resistant OVCAR-5 cells using DIA LC-MS analysis. Our findings suggest that GSN, CALM1, and TXN may be useful biomarkers for predicting chemotherapy response and understanding the mechanisms of chemotherapy resistance. Proteomic data are available via ProteomeXchange with identifier PXD033785.

show abstract

“…A study analyzing the metabolome and proteome in normal and resistant group OC cells revealed perturbations of IFN signaling in resistant group cancer cells. Tyrosine kinase 2 (TYK2), an enzyme that plays a key role in IFN-I signaling, was reduced in abundance in CAOV3 CBPR cells ( 89 ). This conclusion was similarly validated by clinical data showing that patients with high IFN-γ in the immune microenvironment had a better prognosis in platinum-treated patients ( 90 ).…”

Section: The Roles Of Interferons In Oc Treatmentmentioning

confidence: 99%

The role of interferons in ovarian cancer progression: Hinderer or promoter?

Liu

Wang

et al. 2022

Front. Immunol.

View full text Add to dashboard Cite

Ovarian cancer (OC) is a common gynecologic malignancy with poor prognosis and high mortality. Changes in the OC microenvironment are closely related to the genesis, invasion, metastasis, recurrence, and drug-resistance. The OC microenvironment is regulated by Interferons (IFNs) known as a type of important cytokines. IFNs have a bidirectional regulation for OC cells growth and survival. Meanwhile, IFNs positively regulate the recruitment, differentiation and activation of immune cells. This review summarizes the secretion and the role of IFNs. In particular, we mainly elucidate the actions played by IFNs in various types of therapy. IFNs assist radiotherapy, targeted therapy, immunotherapy and biotherapy for OC, except for some IFN pathways that may cause chemo-resistance. In addition, we present some advances in OC treatment with the help of IFN pathways. IFNs have the ability to powerfully modulate the tumor microenvironment and can potentially provide new combination strategies for OC treatment.

show abstract

Chemoresistant Cancer Cell Lines Are Characterized by Migratory, Amino Acid Metabolism, Protein Catabolism and IFN1 Signalling Perturbations

Cited by 6 publications

References 96 publications

Platinum-resistance in epithelial ovarian cancer: an interplay of epithelial–mesenchymal transition interlinked with reprogrammed metabolism

Platinum-resistance in epithelial ovarian cancer: an interplay of epithelial–mesenchymal transition interlinked with reprogrammed metabolism

Label-Free Quantification Mass Spectrometry Identifies Protein Markers of Chemotherapy Response in High-Grade Serous Ovarian Cancer

The role of interferons in ovarian cancer progression: Hinderer or promoter?

Contact Info

Product

Resources

About