Inhibitor of apoptosis proteins (IAPs) may be effective therapeutic targets for treating endometriosis

• Published in: Human reproduction (Oxford) 2015-01, Vol.30 (1), p.149-158
• Main Authors: Uegaki, Takashi, Taniguchi, Fuminori, Nakamura, Kazuomi, Osaki, Mitsuhiko, Okada, Futoshi, Yamamoto, Osamu, Harada, Tasuku
• Format: Article
• Language: English
• Subjects: Animals; Cell Proliferation - drug effects; Endometriosis - genetics; Endometriosis - metabolism; Female; Gene Expression Regulation; Humans; Inhibitor of Apoptosis Proteins - antagonists & inhibitors; Inhibitor of Apoptosis Proteins - genetics; Inhibitor of Apoptosis Proteins - metabolism; Inhibitor of Apoptosis Proteins - physiology; Mice; Mice, Inbred BALB C; Original
• ISSN: 0268-1161; 1460-2350
• DOI: 10.1093/humrep/deu288

STUDY QUESTION What is the role of the inhibitor of apoptosis proteins (IAPs) in human endometriotic tissues and a mouse model of endometriosis? SUMMARY ANSWER Four IAP proteins were expressed in endometriotic tissue indicating IAPs may be a key factor in the pathogenesis and progression of endometriosis. WHAT IS KNOWN ALREADY Overexpression of IAPs protects against a number of proapoptotic stimuli. IAPs (c-IAP1, c-IAP2, XIAP and Survivin) are expressed in human ectopic endometrial stromal cells (ESCs) from ovarian endometriomas. STUDY DESIGN, SIZE, DURATION Forty-eight women with or without ovarian endometrioma are included in this study. BALB/c mice (n = 24) were used for the mouse endometriosis model. Mice with surgically induced endometriosis were treated with an IAP antagonist (BV6) for 4 weeks. PARTICIPANTS/MATERIALS, SETTING, METHODS Human ectopic endometrial tissues from chocolate cysts and eutopic endometrial tissue were collected. ESCs were enzymatically isolated from these tissues. ESC proliferation was examined by 5-bromo-2′-deoxyuridine—enzyme-linked immunosorbent assay. IAPs expression in tissue derived from eutopic endometria and chocolate cysts was evaluated using real-time RT–PCR and immunohistochemistry. A homologous mouse endometriosis model was established by transplanting donor mouse uterine tissue into the abdominal cavities of recipient mice. After treating the mice with BV6 (i.p. 10 mg/ml), the extent of endometriosis-like lesions in mice was measured and proliferative activity assessed by Ki67 staining. All experiments were repeated a minimum of three times. MAIN RESULTS AND THE ROLE OF CHANCE IAP (c-IAP1, c-IAP2, XIAP and Survivin) mRNA and protein in human ectopic endometrial tissues were expressed at higher levels than in eutopic endometrial tissues (P < 0.05). All four IAPs proteins were expressed in mouse endometriosis-like implants. BV6 inhibited BrdU incorporation of human ESCs (P < 0.05 versus control). BV6 also decreased the total number, weight, surface area and Ki67 positive cells in the endometriosis-like lesions in the mice (P < 0.05 versus control). LIMITATIONS, REASONS FOR CAUTION Endometriotic lesions were surgically induced in mice by transplanting mouse uterine tissue only, not human pathological endometriotic tissue. Furthermore, the effects of BV6 on human ESCs and mouse endometriosis-like lesions may differ between the species. WIDER IMPLICATIONS OF THE FINDINGS Our data support the hypothesis that IAPs are inv