Dataset Information

Constitutive activation of integrin ?v?3 contributes to anoikis resistance of ovarian cancer cells.

ABSTRACT: Epithelial ovarian cancer involves the shedding of single tumor cells or spheroids from the primary tumor into ascites, followed by their survival, and transit to the sites of metastatic colonization within the peritoneal cavity. During their flotation, anchorage-dependent epithelial-type tumor cells gain anoikis resistance, implicating integrins, including ?vß3. In this study, we explored anoikis escape, cisplatin resistance, and prosurvival signaling as a function of the ?vß3 transmembrane conformational activation state in cells suspended in ascites. A high-affinity and constitutively signaling-competent ?vß3 variant, which harbored unclasped transmembrane domains, was found to confer delayed anoikis onset, enhanced cisplatin resistance, and reduced cell proliferation in ascites or 3D-hydrogels, involving p27^kip upregulation. Moreover, it promoted EGF-R expression and activation, prosurvival signaling, implicating FAK, src, and PKB/Akt. This led to the induction of the anti-apoptotic factors Bcl-2 and survivin suppressing caspase activation, compared to a signaling-incapable ?vß3 variant displaying firmly associated transmembrane domains. Dissecting the mechanistic players for ?vß3-dependent survival and peritoneal metastasis of ascitic ovarian cancer spheroids is of paramount importance to target their anchorage independence by reversing anoikis resistance and blocking ?vß3-triggered prosurvival signaling.

SUBMITTER: Dolinschek R

PROVIDER: S-EPMC7858284 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Constitutive activation of integrin αvβ3 contributes to anoikis resistance of ovarian cancer cells.

Dolinschek Romana R Hingerl Julia J Benge Anke A Zafiu Christian C Schüren Elisabeth E Ehmoser Eva-Kathrin EK Lössner Daniela D Reuning Ute U

Molecular oncology 20201201 2

Epithelial ovarian cancer involves the shedding of single tumor cells or spheroids from the primary tumor into ascites, followed by their survival, and transit to the sites of metastatic colonization within the peritoneal cavity. During their flotation, anchorage-dependent epithelial-type tumor cells gain anoikis resistance, implicating integrins, including αvß3. In this study, we explored anoikis escape, cisplatin resistance, and prosurvival signaling as a function of the αvß3 transmembrane con ...[more]

PMID: 33155399

Similar Datasets

Project description:This study is to investigate transcription factors involved in cisplatin resistance in ovarian cancer cells. The transcriptome of cisplatin resistant and sensitive A2780 epithelial ovarian cancer cells was obtained from GSE15372. Ovarian transcriptome data GSE62944 was downloaded from TCGA and applied for transcription regulatory network analysis. The analysis results were confirmed using quantitative polymerase chain reaction. The roles of SREBP2 in cisplatin-resistant cells were investigated by RNA inference and cell viability analysis. Transcription regulatory network analysis found that 12 transcription factors and their targets were involved in cisplatin resistant in A2780 cells. Among these factors, the targets of EZH2 and SREBP2 revealed by Transcriptional Regulatory Relationships Unraveled by Sentence-based Text mining were also enriched in differentially expressed genes between cisplatin resistant and cisplatin sensitive cells. Their targets were enriched mainly in cell cycle and cholesterol metabolic process, respectively. Bioinformatic analysis illustrated three known targets of SREBP2, namely LDLR, FDFT1, and HMGCR were increased in A2780-resistant cell lines. Additionally, the three genes and SREBP2 were also elevated in live cells after cisplatin treatment via quantitative polymerase chain reaction. Importantly, RNA inference of SREBP2 in A2780 cell line resulted in a decrease of cell viability after cisplatin treatment. SREBP2 played important roles in cisplatin resistance and cholesterol metabolic process might be a novel target for cancer therapy. Impact statement Transcriptome of cisplatin resistant and sensitive A2780 epithelial ovarian cancer cells was obtained from GSE15372 and TCGA. Twelve transcription factors and their targets were involved in cisplatin resistant. Among these factors, the targets of EZH2 and SREBP2 revealed by Transcriptional Regulatory Relationships Unraveled by Sentence-based Text mining were also enriched in differentially expressed genes. Their targets were enriched mainly in cell cycle and cholesterol metabolic process. Three targets of SREBP2, namely LDLR, FDFT1, and HMGCR were increased in A2780-resistant cell lines and were found elevated in live cells after cisplatin treatment via qPCR. RNAi of SREBP2 in A2780 cell line resulted in a decrease of cell viability after cisplatin treatment. SREBP2 played important roles in cisplatin resistance and might be a novel target for cancer therapy.

Dataset Information

Constitutive activation of integrin ?v?3 contributes to anoikis resistance of ovarian cancer cells.

Publications

Constitutive activation of integrin αvβ3 contributes to anoikis resistance of ovarian cancer cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure