GPER deletion triggers inhibitory effects in triple negative breast cancer (TNBC) cells through the JNK/c-Jun/p53/Noxa transduction pathway.

Autor: Cirillo F; Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036, Rende, Italy., Talia M; Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036, Rende, Italy., Santolla MF; Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036, Rende, Italy., Pellegrino M; Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036, Rende, Italy., Scordamaglia D; Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036, Rende, Italy., Spinelli A; Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036, Rende, Italy., De Rosis S; Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036, Rende, Italy., Giordano F; Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036, Rende, Italy., Muglia L; Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036, Rende, Italy., Zicarelli A; Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036, Rende, Italy., Di Dio M; Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036, Rende, Italy., Rigiracciolo DC; Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Via Adamello 16, 20139, Milano, Italy., Miglietta AM; Breast and General Surgery Unit, Regional Hospital Cosenza, 87100, Cosenza, Italy., Filippelli G; Oncology Department, Hospital of Paola, 87100, Cosenza, Italy., De Francesco EM; Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, 95122, Catania, Italy., Belfiore A; Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, 95122, Catania, Italy., Lappano R; Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036, Rende, Italy. rosamaria.lappano@unical.it., Maggiolini M; Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036, Rende, Italy. marcello.maggiolini@unical.it.
Jazyk: angličtina
Zdroj: Cell death discovery [Cell Death Discov] 2023 Sep 26; Vol. 9 (1), pp. 353. Date of Electronic Publication: 2023 Sep 26.
DOI: 10.1038/s41420-023-01654-0
Abstrakt: The G protein-coupled estrogen receptor (GPER) mediates estrogen action in different pathophysiological conditions, including cancer. GPER expression and signaling have been found to join in the progression of triple-negative breast cancer (TNBC), even though controversial data have been reported. In present study, we aimed at providing new mechanistic and biological discoveries knocking out (KO) GPER expression by CRISPR/Cas9 technology in MDA-MB-231 TNBC cells. GPER KO whole transcriptome respect to wild type (WT) MDA-MB-231 cells was determined through total RNA sequencing (RNA-Seq) and gene ontology (GO) enrichment analysis. We ascertained that anti-proliferative and pro-apoptotic gene signatures characterize GPER KO MDA-MB-231 cells. Thereafter, we determined that these cells exhibit a reduced proliferative, clonogenic and self-renewal potential along with an increased mitochondria-dependent apoptosis phenotype. In addition, we recognized that decreased cAMP levels trigger the JNK/c-Jun/p53/Noxa axis, which in turn orchestrates the pro-apoptotic effects observed in GPER KO cells. In accordance with these data, survival analyses in TNBC patients of the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset indicated that high Noxa expression correlates with improved outcomes in TNBC patients. Furthermore, we demonstrated that GPER KO in TNBC cells impairs the expression and secretion of the well-acknowledged GPER target gene named CTGF, thus resulting in the inhibition of migratory effects in cancer-associated fibroblasts (CAFs). Overall, the present study provides novel mechanistic and biological insights on GPER KO in TNBC cells suggesting that GPER may be considered as a valuable target in comprehensive therapeutic approaches halting TNBC progression.
(© 2023. Cell Death Differentiation Association (ADMC).)
Databáze: MEDLINE
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