title: Anti-Müllerian hormone inhibits growth of AMH type II receptor-positive human ovarian granulosa cell tumor cells by activating apoptosis.
abstract: Ovarian granulosa cell tumors (GCTs) are sex cord stromal tumors that constitute 3-5% of all ovarian cancers. GCTs usually present with an indolent course but there is a high risk of recurrence, which associates with increased mortality, and targeted treatments would be desirable. Anti-Müllerian hormone (AMH), a key factor regulating sexual differentiation of the reproductive organs, has been implicated as a growth inhibitor in ovarian cancer. GCTs and normal granulosa cells produce AMH, but its expression in large GCTs is usually downregulated. Further, as the lack of specific AMH-signaling pathway components leads to GCT development in mice, we hypothesized that AMH inhibits growth of GCTs. Utilizing a large panel of human GCT tissue samples, we found that AMH type I receptors (ALK2, ALK3 and ALK6) and type II receptor (AMHRII), as well as their downstream effectors Smad1/5, are expressed and active in GCTs. AMHRII expression was detected in the vast majority (96%) of GCTs and correlated with AMH mRNA and protein expression. AMH mRNA level was low in large GCTs, confirming previous findings on low-AMH protein expression in large human as well as mouse GCTs. To study the functional role of AMH in this peculiar ovarian cancer, we utilized a human GCT cell line (KGN) and 10 primary GCT cell cultures. We found that the AMH-Smad1/5-signaling pathway was active in these cells, and that exogenous AMH further activated Smad1/5 in KGN cells. Furthermore, AMH treatment reduced the number of KGN cells and primary GCT cells, with increasing amounts of AMH leading to augmented activation of caspase-3 and subsequent apoptosis. All in all, these data support the premise that AMH is a growth inhibitor of GCTs.
authors.affiliation: Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Finland. mikko.anttonen@helsinki.fi
authors.forename: Mikko
authors.initials: M
authors.lastname: Anttonen
authors.forename: Anniina
authors.initials: A
authors.lastname: Färkkilä
authors.forename: Hanna
authors.initials: H
authors.lastname: Tauriala
authors.forename: Marjut
authors.initials: M
authors.lastname: Kauppinen
authors.forename: David T
authors.initials: DT
authors.lastname: Maclaughlin
authors.forename: Leila
authors.initials: L
authors.lastname: Unkila-Kallio
authors.forename: Ralf
authors.initials: R
authors.lastname: Bützow
authors.forename: Markku
authors.initials: M
authors.lastname: Heikinheimo
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D054304:Anti-Mullerian Hormone / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D001973:Bromodeoxyuridine; D045744:Cell Line, Tumor; D017931:DNA Primers / Q000235:genetics; D005260:Female; D006106:Granulosa Cell Tumor / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D018000:Receptors, Peptide / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013778:Tetrazolium Salts; D013844:Thiazoles
chemical_list: D017931:DNA Primers; D018000:Receptors, Peptide; D018125:Receptors, Transforming Growth Factor beta; D013778:Tetrazolium Salts; D013844:Thiazoles; C084621:anti-Mullerian hormone receptor; D054304:Anti-Mullerian Hormone; C022616:thiazolyl blue; D001973:Bromodeoxyuridine