Naringenin induces mitochondria-mediated apoptosis and endoplasmic reticulum stress by regulating MAPK and AKT signal transduction pathways in endometriosis cells.

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: Sunwoo Park, Whasun Lim, Fuller W Bazer, Gwonhwa Song
• Journal: Molecular human reproduction (Mol Hum Reprod) Vol. 23 Issue 12 Pg. 842-854 (12 01 2017) ISSN: 1460-2407 [Electronic] England
• PMID: 29121349 (Publication Type: Journal Article)
• Copyright: © The Author 2017. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email:[email protected]

Chemical References

• Annexin A5
• BAK1 protein, human
• BAX protein, human
• DDIT3 protein, human
• Endoplasmic Reticulum Chaperone BiP
• Estrogen Antagonists
• Eukaryotic Initiation Factor-2
• Flavanones
• HSPA5 protein, human
• Heat-Shock Proteins
• Phosphoinositide-3 Kinase Inhibitors
• Reactive Oxygen Species
• bcl-2 Homologous Antagonist-Killer Protein
• bcl-2-Associated X Protein
• Transcription Factor CHOP
• ERN1 protein, human
• Protein Serine-Threonine Kinases
• Mitogen-Activated Protein Kinases
• Endoribonucleases
• naringenin

Topics

• Annexin A5 (genetics, metabolism)
• Apoptosis (drug effects)
• Cell Line
• Dose-Response Relationship, Drug
• Endometriosis (metabolism, pathology)
• Endometrium (metabolism, pathology)
• Endoplasmic Reticulum Chaperone BiP
• Endoplasmic Reticulum Stress (drug effects)
• Endoribonucleases (genetics, metabolism)
• Estrogen Antagonists (pharmacology)
• Eukaryotic Initiation Factor-2 (agonists, genetics, metabolism)
• Female
• Flavanones (pharmacology)
• Gene Expression Regulation
• Heat-Shock Proteins (agonists, genetics, metabolism)
• Humans
• Membrane Potential, Mitochondrial (drug effects)
• Mitochondria (drug effects, metabolism)
• Mitogen-Activated Protein Kinases (genetics, metabolism)
• Phosphatidylinositol 3-Kinases (genetics, metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Reactive Oxygen Species (agonists, metabolism)
• Signal Transduction
• Stromal Cells (drug effects, metabolism, pathology)
• Transcription Factor CHOP (agonists, genetics, metabolism)
• bcl-2 Homologous Antagonist-Killer Protein (agonists, genetics, metabolism)
• bcl-2-Associated X Protein (agonists, genetics, metabolism)