The G-Protein-Coupled Estrogen Receptor Agonist G-1 Mediates Antitumor Effects by Activating Apoptosis Pathways and Regulating Migration and Invasion in Cervical Cancer Cells

• Published in: Cancers 2024-09, Vol.16 (19), p.3292
• Main Authors: Gaxiola-Rubio, Abigail, Jave-Suárez, Luis Felipe, Hernández-Silva, Christian David, Ramírez-de-Arellano, Adrián, Villegas-Pineda, Julio César, Lizárraga-Ledesma, Marisa de Jesús, Ramos-Solano, Moisés, Diaz-Palomera, Carlos Daniel, Pereira-Suárez, Ana Laura
• Format: Article
• Language: English
• Subjects: Agonists; Angiogenesis; Antitumor activity; Apoptosis; Cell activation; Cell cycle; Cell migration; Cell proliferation; Cervical cancer; Cloning; Dkk1 protein; Estrogen receptors; Estrogens; Human papillomavirus; Keratinocytes; Localization; Molecular modelling; Oncogenes; Oxidative metabolism; Oxidative phosphorylation; Phosphorylation; Proteins; Roles; Signal transduction; Transcriptomes; Tumor cell lines; Tumor necrosis factor-α; Tumors; Ultraviolet radiation; Vimentin
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers16193292

Estrogens and HPV are necessary for cervical cancer (CC) development. The levels of the G protein-coupled estrogen receptor (GPER) increase as CC progresses, and HPV oncoproteins promote GPER expression. The role of this receptor is controversial due to its anti- and pro-tumor effects. This study aimed to determine the effect of GPER activation, using its agonist G-1, on the transcriptome, cell migration, and invasion in SiHa cells and non-tumorigenic keratinocytes transduced with the HPV16 E6 or E7 oncogenes. Transcriptome analysis was performed to identify G-1-enriched pathways in SiHa cells. We evaluated cell migration, invasion, and the expression of associated proteins in SiHa, HaCaT-16E6, and HaCaT-16E7 cells using various assays. Transcriptome analysis revealed pathways associated with proliferation/apoptosis (TNF-α signaling, UV radiation response, mitotic spindle formation, G2/M cell cycle, UPR, and IL-6/JAK/STAT), cellular metabolism (oxidative phosphorylation), and cell migration (angiogenesis, EMT, and TGF-α signaling) in SiHa cells. Key differentially expressed genes included PTGS2 (pro/antitumor), FOSL1, TNFRSF9, IL1B, DIO2, and PHLDA1 (antitumor), along with under-expressed genes with pro-tumor effects that may inhibit proliferation. Additionally, DKK1 overexpression suggested inhibition of cell migration. G-1 increased vimentin expression in SiHa cells and reduced it in HaCaT-16E6 and HaCaT-16E7 cells. However, G-1 did not affect α-SMA expression or cell migration in any of the cell lines but increased invasion in HaCaT-16E7 cells. GPER is a promising prognostic marker due to its ability to activate apoptosis and inhibit proliferation without promoting migration/invasion in CC cells. G-1 could potentially be a tool in the treatment of this neoplasia.