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Naringenin induces mitochondria-mediated apoptosis and endoplasmic reticulum stress by regulating MAPK and AKT signal transduction pathways in endometriosis cells.
Mol Hum Reprod. 2017 12 01; 23(12):842-854.MH

Abstract

STUDY QUESTION

Does the flavonoid naringenin inhibit proliferation of human endometriosis cells?

SUMMARY ANSWER

Naringenin suppresses proliferation and increases apoptosis via depolarization of mitochondrial membrane potential and generation of reactive oxygen species (ROS) in human endometriosis cells.

WHAT IS KNOWN ALREADY

For management of endometriosis, hormonal therapy is commonly used to decrease production of estrogens by the ovaries, but that has limitations including undesirable side effects with long-term therapies. To overcome these limitations, it is important to discover novel compounds which have no adverse effects, but inhibit expression of target molecules involved in the pathogenesis of endometriosis.

STUDY DESIGN SIZE, DURATION

Well-established endometriosis cell lines (VK2/E6E7 and End1/E6E7) were purchased from the American Type Culture Collection. Effects of naringenin on VK2/E6E7 and End1/E6E7 cells were assessed in diverse assays in a dose- and time-dependent manner.

PARTICIPANTS/MATERIALS, SETTING, METHODS

Effects of naringenin on viability, apoptosis (Annexin V expression, propidium iodide staining, TUNEL and invasion assays), mitochondria-mediated apoptosis, production of ROS and endoplasmic reticulum (ER) stress proteins of VK2/E6E7 and End1/E6E7 cells were determined. Signal transduction pathways in VK2/E6E7 and End1/E6E7 cells in response to naringenin were determined by western blot analyses.

MAIN RESULTS AND THE ROLE OF CHANCE

In the present study, we demonstrated that naringenin suppressed proliferation and increased apoptosis through depolarization of mitochondrial membrane potential and inducing pro-apoptotic proteins, Bax and Bak, in both endometriosis cell lines. In addition, naringenin increased ROS, ER stress, through activation of eIF2α and IRE1α, GADD153 and GRP78 proteins in a dose-dependent manner. Furthermore, the induction of apoptosis by naringenin involved activation of MAPK and inactivation of PI3K pathways in VK2/E6E7 and End1/E6E7 cells.

LIMITATIONS REASONS FOR CAUTION

Lack of in vivo animal studies is a major limitation of this research. Effectiveness of naringenin to induce apoptosis of human endometriosis cells requires further investigation.

WIDER IMPLICATIONS OF THE FINDINGS

Our results suggest that naringenin is a promising therapeutic compound for treatment of endometriosis in women.

STUDY FUNDING/COMPETING INTEREST(S)

This work was supported by grants from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (No. HI15C0810 awarded to G.S. and HI17C0929 awarded to W.L.). The authors declare that there are no conflicts of interest.

Authors+Show Affiliations

Institute of Animal Molecular Biotechnology and Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Rm 310, Life Science Building (West), 145, Anam-ro, Seongbuk-gu, Seoul, Republic of Korea.Department of Biomedical Sciences, Catholic Kwandong University, Rm 420, Cheongsong Building, 24, Beomil-ro 579beon-gil, Gangneung-si, Republic of Korea.Center for Animal Biotechnology and Genomics and Department of Animal Science, Texas A&M University, Rm 442D, Kleberg Center, College Station, TX, USA.Institute of Animal Molecular Biotechnology and Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Rm 310, Life Science Building (West), 145, Anam-ro, Seongbuk-gu, Seoul, Republic of Korea.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29121349

Citation

Park, Sunwoo, et al. "Naringenin Induces Mitochondria-mediated Apoptosis and Endoplasmic Reticulum Stress By Regulating MAPK and AKT Signal Transduction Pathways in Endometriosis Cells." Molecular Human Reproduction, vol. 23, no. 12, 2017, pp. 842-854.
Park S, Lim W, Bazer FW, et al. Naringenin induces mitochondria-mediated apoptosis and endoplasmic reticulum stress by regulating MAPK and AKT signal transduction pathways in endometriosis cells. Mol Hum Reprod. 2017;23(12):842-854.
Park, S., Lim, W., Bazer, F. W., & Song, G. (2017). Naringenin induces mitochondria-mediated apoptosis and endoplasmic reticulum stress by regulating MAPK and AKT signal transduction pathways in endometriosis cells. Molecular Human Reproduction, 23(12), 842-854. https://doi.org/10.1093/molehr/gax057
Park S, et al. Naringenin Induces Mitochondria-mediated Apoptosis and Endoplasmic Reticulum Stress By Regulating MAPK and AKT Signal Transduction Pathways in Endometriosis Cells. Mol Hum Reprod. 2017 12 1;23(12):842-854. PubMed PMID: 29121349.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Naringenin induces mitochondria-mediated apoptosis and endoplasmic reticulum stress by regulating MAPK and AKT signal transduction pathways in endometriosis cells. AU - Park,Sunwoo, AU - Lim,Whasun, AU - Bazer,Fuller W, AU - Song,Gwonhwa, PY - 2017/03/21/received PY - 2017/10/31/accepted PY - 2017/11/10/pubmed PY - 2018/7/19/medline PY - 2017/11/10/entrez KW - ER stress KW - ROS KW - apoptosis KW - endometriosis KW - naringenin SP - 842 EP - 854 JF - Molecular human reproduction JO - Mol Hum Reprod VL - 23 IS - 12 N2 - STUDY QUESTION: Does the flavonoid naringenin inhibit proliferation of human endometriosis cells? SUMMARY ANSWER: Naringenin suppresses proliferation and increases apoptosis via depolarization of mitochondrial membrane potential and generation of reactive oxygen species (ROS) in human endometriosis cells. WHAT IS KNOWN ALREADY: For management of endometriosis, hormonal therapy is commonly used to decrease production of estrogens by the ovaries, but that has limitations including undesirable side effects with long-term therapies. To overcome these limitations, it is important to discover novel compounds which have no adverse effects, but inhibit expression of target molecules involved in the pathogenesis of endometriosis. STUDY DESIGN SIZE, DURATION: Well-established endometriosis cell lines (VK2/E6E7 and End1/E6E7) were purchased from the American Type Culture Collection. Effects of naringenin on VK2/E6E7 and End1/E6E7 cells were assessed in diverse assays in a dose- and time-dependent manner. PARTICIPANTS/MATERIALS, SETTING, METHODS: Effects of naringenin on viability, apoptosis (Annexin V expression, propidium iodide staining, TUNEL and invasion assays), mitochondria-mediated apoptosis, production of ROS and endoplasmic reticulum (ER) stress proteins of VK2/E6E7 and End1/E6E7 cells were determined. Signal transduction pathways in VK2/E6E7 and End1/E6E7 cells in response to naringenin were determined by western blot analyses. MAIN RESULTS AND THE ROLE OF CHANCE: In the present study, we demonstrated that naringenin suppressed proliferation and increased apoptosis through depolarization of mitochondrial membrane potential and inducing pro-apoptotic proteins, Bax and Bak, in both endometriosis cell lines. In addition, naringenin increased ROS, ER stress, through activation of eIF2α and IRE1α, GADD153 and GRP78 proteins in a dose-dependent manner. Furthermore, the induction of apoptosis by naringenin involved activation of MAPK and inactivation of PI3K pathways in VK2/E6E7 and End1/E6E7 cells. LIMITATIONS REASONS FOR CAUTION: Lack of in vivo animal studies is a major limitation of this research. Effectiveness of naringenin to induce apoptosis of human endometriosis cells requires further investigation. WIDER IMPLICATIONS OF THE FINDINGS: Our results suggest that naringenin is a promising therapeutic compound for treatment of endometriosis in women. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by grants from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (No. HI15C0810 awarded to G.S. and HI17C0929 awarded to W.L.). The authors declare that there are no conflicts of interest. SN - 1460-2407 UR - https://www.unboundmedicine.com/medline/citation/29121349/Naringenin_induces_mitochondria_mediated_apoptosis_and_endoplasmic_reticulum_stress_by_regulating_MAPK_and_AKT_signal_transduction_pathways_in_endometriosis_cells_ L2 - https://academic.oup.com/molehr/article-lookup/doi/10.1093/molehr/gax057 DB - PRIME DP - Unbound Medicine ER -