The activation of M2 muscarinic receptor inhibits cell growth and survival in human epithelial ovarian carcinoma

Abstract

Ovarian cancer is the fifth leading cause of cancer-related deaths in females.Many ovarian tumor cell lines express muscarinic receptors (mAChRs), and their expression is correlated with reduced survival of patients. We have characterized the expression of mAChRs in two human ovarian carcinoma cell lines (SKOV-3, TOV-21G) and two immortalized ovarian surface epithelium cell lines (iOSE-120, iOSE-398). Among the five subtypes of mAChRs (M1-M5 receptors), we focused our attention on the M2 receptor, which is involved in the inhibition of tumor cell proliferation. Western blot analysis and real-time PCR analyses indicated that the levels of M2 are statistically downregulated in cancer cells. Therefore, we investigated the effect of arecaidine propargyl ester hydrobromide (APE), a preferential M2 agonist, on cell growth and survival. APE treatment decreased cell number in a dose and time-dependent manner by decreasing cell proliferation and increasing cell death. FACS and immunocytochemistry analysis have also demonstrated the ability of APE to accumulate the cells in G2/M phase of the cell cycle and to increase the percentage of abnormal mitosis. The higher level of M2 receptors in the iOSE cells rendered these cells more sensitive to APE treatment than cancer cells.The data here reported suggest that M2 has a negative role in cell growth/ survival of ovarian cell lines, and its downregulation may favor tumor progression.

M2 Muscarinic Receptor Stimulation Induces Autophagy in Human Glioblastoma Cancer Stem Cells via mTOR Complex-1 Inhibition

“…Over the past decade, various studies have shown that the activation of mAChRs is critical in the regulation of cell proliferation and cancer progression [ 43 ]. In this context, we have been studying the role of the M2 mAChR in cancer for many years, demonstrating that activation of this receptor subtype brings about anti-proliferative and cytotoxic effects on cells of different tumor types such as ovarian cancer [ 19 ], breast cancer [ 18 ], neuroblastoma [ 21 ] and GBM [ 32 ]. For GBM, we showed that in the U251 cell line, the activation of M2 mAChRs by the orthosteric agonist APE caused cell cycle arrest as well as progressive accumulation of the cells in the G2/M phase [ 24 ].…”

“…mAChRs are G protein-coupled receptors (GPCRs) involved in the regulation of several fundamental processes in both central and peripheral nervous systems [ 17 ]. Moreover, the expression of mAChRs in different tumors and their strategic role in the modulation of cancer cell proliferation, survival and migration have been demonstrated [ 18 , 19 , 20 , 21 , 22 ]. In this framework, we have demonstrated that the activation of M2 mAChR by the orthosteric M2 agonist Arecaidine Propargyl Ester (APE) has negative effects on cell proliferation and survival, both in GBM cell lines and in GBM cancer stem cells (GSCs) [ 23 , 24 ].…”

Multitargeting nature of muscarinic orthosteric agonists and antagonists

“…In this review, we will focus on mAChRs. As an example, the recent translational research of human epithelial ovarian carcinoma have described the role of M 2 mAChRs in M 2 cell growth and survival ( Taggi et al, 2022 ). The authors have used arecaidine propargyl ester as M 2 mAChR preferential agonist.…”