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Inhibitor of apoptosis proteins (IAPs) may be effective therapeutic targets for treating endometriosis.
Hum Reprod. 2015 Jan; 30(1):149-58.HR

Abstract

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 involved in the development of endometriosis, and therefore an inhibitor of IAPs has potential as a novel treatment for endometriosis.

STUDY FUNDING/COMPETING INTERESTS

This work was supported by KAKENHI (Japan Society for the Promotion of Science, Grant-in-Aid: to F.T.; 21592098 and to T.H.; 24659731) and Yamaguchi Endocrine Research Foundation. The authors have no conflicts of interest to disclose.

Authors+Show Affiliations

Department of Obstetrics and Gynecology, Tottori University Faculty of Medicine, 36-1 Nishi-cho, Yonago 683-8504, Japan.Department of Obstetrics and Gynecology, Tottori University Faculty of Medicine, 36-1 Nishi-cho, Yonago 683-8504, Japan tani4327@med.tottori-u.ac.jp.Division of Laboratory Animal Science, Research Center for Bioscience and Technology, Tottori University Faculty of Medicine, Yonago, Japan.Pathological Biochemistry, Tottori University Faculty of Medicine, Yonago, Japan.Pathological Biochemistry, Tottori University Faculty of Medicine, Yonago, Japan.Dermatology, Tottori University Faculty of Medicine, Yonago, Japan.Department of Obstetrics and Gynecology, Tottori University Faculty of Medicine, 36-1 Nishi-cho, Yonago 683-8504, Japan.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25376458

Citation

Uegaki, Takashi, et al. "Inhibitor of Apoptosis Proteins (IAPs) May Be Effective Therapeutic Targets for Treating Endometriosis." Human Reproduction (Oxford, England), vol. 30, no. 1, 2015, pp. 149-58.
Uegaki T, Taniguchi F, Nakamura K, et al. Inhibitor of apoptosis proteins (IAPs) may be effective therapeutic targets for treating endometriosis. Hum Reprod. 2015;30(1):149-58.
Uegaki, T., Taniguchi, F., Nakamura, K., Osaki, M., Okada, F., Yamamoto, O., & Harada, T. (2015). Inhibitor of apoptosis proteins (IAPs) may be effective therapeutic targets for treating endometriosis. Human Reproduction (Oxford, England), 30(1), 149-58. https://doi.org/10.1093/humrep/deu288
Uegaki T, et al. Inhibitor of Apoptosis Proteins (IAPs) May Be Effective Therapeutic Targets for Treating Endometriosis. Hum Reprod. 2015;30(1):149-58. PubMed PMID: 25376458.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibitor of apoptosis proteins (IAPs) may be effective therapeutic targets for treating endometriosis. AU - Uegaki,Takashi, AU - Taniguchi,Fuminori, AU - Nakamura,Kazuomi, AU - Osaki,Mitsuhiko, AU - Okada,Futoshi, AU - Yamamoto,Osamu, AU - Harada,Tasuku, Y1 - 2014/11/05/ PY - 2014/11/8/entrez PY - 2014/11/8/pubmed PY - 2016/4/5/medline KW - BV6 KW - endometrial stromal cells KW - inhibitor of apoptosis proteins family KW - mouse endometriosis model SP - 149 EP - 58 JF - Human reproduction (Oxford, England) JO - Hum. Reprod. VL - 30 IS - 1 N2 - 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 involved in the development of endometriosis, and therefore an inhibitor of IAPs has potential as a novel treatment for endometriosis. STUDY FUNDING/COMPETING INTERESTS: This work was supported by KAKENHI (Japan Society for the Promotion of Science, Grant-in-Aid: to F.T.; 21592098 and to T.H.; 24659731) and Yamaguchi Endocrine Research Foundation. The authors have no conflicts of interest to disclose. SN - 1460-2350 UR - https://www.unboundmedicine.com/medline/citation/25376458/Inhibitor_of_apoptosis_proteins__IAPs__may_be_effective_therapeutic_targets_for_treating_endometriosis_ L2 - https://academic.oup.com/humrep/article-lookup/doi/10.1093/humrep/deu288 DB - PRIME DP - Unbound Medicine ER -