Mullerian inhibiting substance induces apoptosis of human endometrial stromal cells in endometriosis.

Abstract

CONTEXT:

Müllerian inhibiting substance (MIS) is produced in Sertoli cells of fetal testis and causes regression of müllerian ducts in male embryos. MIS also can induce the cell cycle arrest and apoptosis in müllerian duct-derived tumors in vivo and in vitro.

OBJECTIVE:

Our objective was to investigate the expression of MIS type II receptor (MISR II) and whether MIS can inhibit the proliferation and induce apoptosis in primary cultures of endometrial stromal cells (ESC) of endometriosis.

DESIGN AND SETTINGS:

In vitro experiments were performed in the university research laboratory.

PARTICIPANTS:

Tissue samples from 12 patients who had undergone evisceration for ovarian endometrial cysts were included in this study.

INTERVENTIONS AND MAIN OUTCOME MEASURES:

The expression of MISR II in ESC was investigated by immunohistochemistry. The cell viability and apoptosis in ESC treated with MIS was measured by methylthiazoletetrazolium assay and annexin V analysis. The expression of regulatory proteins in ESC treated with MIS was shown by Western blotting.

RESULTS:

ESC showed specific immunostaining for the MISR II. ESC treated with MIS exhibited 32% growth inhibition (P = 0.0001). The changes in cell cycle distribution after MIS exposure at 72 h demonstrated that S and G(2)M phases were decreased; G(0)G(1) and sub-G(0)G(1) phases were increased. ESC treated with MIS showed 13.72% annexin V-fluorescein isothiocyanate positivity. In the ESCs, which contain defective p16, MIS increased the expression of pocket proteins p107 and p130 and decreased E2F transcription factor 1.

CONCLUSIONS:

The results support a central role for MIS in endometriosis. Although the precise mechanism of MIS-mediated inhibition of ESC growth has not been fully defined, these data suggest that MIS has activity against ESC in vitro and may also be an effective targeted therapy for endometriosis.

• Authors: Jeong Namkung, Jae Yen Song, Hyun Hee Jo, Mee Ran Kim, Young Oak Lew, Patricia K Donahoe, David T MacLaughlin, Jang Heub Kim
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 97 Issue 9 Pg. 3224-30 (Sep 2012) ISSN: 1945-7197 [Electronic] United States
• PMID: 22761458 (Publication Type: Journal Article)

Chemical References

• Annexin A5
• E2F Transcription Factors
• Receptors, Peptide
• Receptors, Transforming Growth Factor beta
• Retinoblastoma-Like Protein p107
• Retinoblastoma-Like Protein p130
• Tetrazolium Salts
• Thiazoles
• anti-Mullerian hormone receptor
• Anti-Mullerian Hormone
• thiazolyl blue

Topics

• Annexin A5 (analysis, metabolism)
• Anti-Mullerian Hormone (pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cells, Cultured
• E2F Transcription Factors (genetics)
• Endometriosis (metabolism, pathology)
• Endometrium (cytology, drug effects, metabolism)
• Female
• Humans
• Immunohistochemistry
• Receptors, Peptide (drug effects, metabolism)
• Receptors, Transforming Growth Factor beta (drug effects, metabolism)
• Retinoblastoma-Like Protein p107 (biosynthesis)
• Retinoblastoma-Like Protein p130 (biosynthesis)
• Stromal Cells (drug effects, metabolism)
• Tetrazolium Salts
• Thiazoles
• Uterine Cervical Neoplasms (pathology)