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: Mikko Anttonen, Anniina Färkkilä, Hanna Tauriala, Marjut Kauppinen, David T Maclaughlin, Leila Unkila-Kallio, Ralf Bützow, Markku Heikinheimo
• Journal: Laboratory investigation; a journal of technical methods and pathology (Lab Invest) Vol. 91 Issue 11 Pg. 1605-14 (Nov 2011) ISSN: 1530-0307 [Electronic] United States
• PMID: 21808236 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA Primers
• Receptors, Peptide
• Receptors, Transforming Growth Factor beta
• Tetrazolium Salts
• Thiazoles
• anti-Mullerian hormone receptor
• Anti-Mullerian Hormone
• thiazolyl blue
• Bromodeoxyuridine

Topics

• Analysis of Variance
• Animals
• Anti-Mullerian Hormone (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Bromodeoxyuridine
• Cell Line, Tumor
• DNA Primers (genetics)
• Female
• Granulosa Cell Tumor (drug therapy, metabolism, physiopathology)
• Humans
• Immunohistochemistry
• Mice
• Ovarian Neoplasms (drug therapy, metabolism, physiopathology)
• Receptors, Peptide (metabolism)
• Receptors, Transforming Growth Factor beta (metabolism)
• Signal Transduction (drug effects)
• Tetrazolium Salts
• Thiazoles