Anti-Müllerian hormone (AMH) autocrine signaling promotes survival and proliferation of ovarian cancer cells
Open Access
- 26 January 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Scientific Reports
- Vol. 11 (1), 1-10
- https://doi.org/10.1038/s41598-021-81819-y
Abstract
In ovarian carcinoma, anti-Müllerian hormone (AMH) type II receptor (AMHRII) and the AMH/AMHRII signaling pathway are potential therapeutic targets. Here, AMH dose-dependent effect on signaling and proliferation was analyzed in four ovarian cancer cell lines, including sex cord stromal/granulosa cell tumors and high grade serous adenocarcinomas (COV434-AMHRII, SKOV3-AMHRII, OVCAR8 and KGN). As previously shown, incubation with exogenous AMH at concentrations above the physiological range (12.5–25 nM) decreased cell viability. Conversely, physiological concentrations of endogenous AMH improved cancer cell viability. Partial AMH depletion by siRNAs was sufficient to reduce cell viability in all four cell lines, by 20% (OVCAR8 cells) to 40% (COV434-AMHRII cells). In the presence of AMH concentrations within the physiological range (5 to 15 pM), the newly developed anti-AMH B10 antibody decreased by 25% (OVCAR8) to 50% (KGN) cell viability at concentrations ranging between 3 and 333 nM. At 70 nM, B10 reduced clonogenic survival by 57.5%, 57.1%, 64.7% and 37.5% in COV434-AMHRII, SKOV3-AMHRII, OVCAR8 and KGN cells, respectively. In the four cell lines, B10 reduced AKT phosphorylation, and increased PARP and caspase 3 cleavage. These results were confirmed in ovarian cancer cells isolated from patients’ ascites, demonstrating the translational potential of these results. Furthermore, B10 reduced COV434-MISRII tumor growth in vivo and significantly enhanced the median survival time compared with vehicle (69 vs 60 days; p = 0.0173). Our data provide evidence for a novel pro-survival autocrine role of AMH in the context of ovarian cancer, which was targeted therapeutically using an anti-AMH antibody to successfully repress tumor growth.Funding Information
- Agence Nationale de la Recherche (ANR-10-LABX-53)
- Ligue Nationale Contre le Cancer, France
- SIRIC Montpellier-Cancer (INCa-DGOS-Inserm 6045)
- INSERM-transfert, France
This publication has 45 references indexed in Scilit:
- Human ovarian cancer stem/progenitor cells are stimulated by doxorubicin but inhibited by Mullerian inhibiting substanceProceedings of the National Academy of Sciences of the United States of America, 2012
- A mesenchymal perspective of müllerian duct differentiation and regression in Amhr2‐lacZ miceMolecular Reproduction and Development, 2008
- A focused antibody library for selecting scFvs expressed at high levels in the cytoplasmBMC Biotechnology, 2007
- YWK-II protein as a novel Go-coupled receptor for Müllerian inhibiting substance in cell survivalJournal of Cell Science, 2007
- Recombinant Human Mullerian Inhibiting Substance Inhibits Long-term Growth of MIS Type II Receptor–Directed Transgenic Mouse Ovarian Cancers In vivoClinical Cancer Research, 2006
- Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti–tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: A randomized, placebo‐controlled, 52‐week trialArthritis & Rheumatism, 2004
- Anti-Müllerian hormone, β-catenin and Müllerian duct regressionMolecular and Cellular Endocrinology, 2003
- Anti-Müllerian hormone in early human developmentEarly Human Development, 1993
- Isolation of the bovine and human genes for müllerian inhibiting substance and expression of the human gene in animal cellsCell, 1986
- Müllerian Duct Regression in the Embryo Correlated with Cytotoxic Activity Against Human Ovarian CancerScience, 1979