Ameliorative effects of luteolin against endometriosis progression in vitro and in vivo

Sunwoo Park; Whasun Lim; Seungkwon You; Gwonhwa Song

doi:10.1016/j.jnutbio.2019.02.006

Ameliorative effects of luteolin against endometriosis progression in vitro and in vivo

Sunwoo Park, Whasun Lim, Seungkwon You, Gwonhwa Song

Department of Biotechnology

Research output: Contribution to journal › Article › peer-review

18 Citations (Scopus)

Abstract

Endometriosis is a common gynecological disease in reproductive-aged women. Generally, accumulation of backflow and debris of endometrial tissue develops into a lesion outside of the endometrium, inducing severe pelvic pain and infertility in some patients. Hormone therapy and surgery are the main treatments available, but various therapeutic phytochemicals are being reviewed in animal studies or clinical trials for endometriosis patients nowadays. However, the therapeutic effects of luteolin in human endometriosis have not been studied well. Here, we demonstrate that luteolin exerts antiproliferative and apoptotic effects in human VK2/E6E7 and End1/E6E7 and in an animal endometriosis model. Luteolin inhibits cell proliferation through cell cycle arrest and induces apoptosis through DNA fragmentation in VK2/E6E7 and End1/E6E7 cells. Cytosolic calcium levels, ROS production and lipid peroxidation also increased dose-dependently (0, 5, 10 and 20 μM) in the treatment with luteolin. In VK2/E6E7 and End1/E6E7 cells, luteolin decreased ERK1/2, JNK and PI3K/AKT signal proteins while activating P38. In addition, intraperitoneal injection of luteolin in the endometriosis mouse model reduced lesion size compared to vehicle-injected mice. Ccne1, Cdk2 and Cdk4 were significantly down-regulated in the autoimplanted endometriosis lesions of mice intraperitoneally injected with luteolin. Knockdown of CCNE1 mRNA in VK2/E6E7 and End1/E6E7 cells decreased cell viability through inhibition of G0/G1 phase progression and increased apoptosis. Together, our results imply that luteolin suppresses endometriosis development by regulation of the PI3K/AKT and MAPK signal proteins as well as the expression of CCNE1 in vitro and in vivo.

Original language	English
Pages (from-to)	161-172
Number of pages	12
Journal	Journal of Nutritional Biochemistry
Volume	67
DOIs	https://doi.org/10.1016/j.jnutbio.2019.02.006
Publication status	Published - 2019 May

Bibliographical note

Funding Information:
This work was supported by the National Research Foundation of Korea grant funded by the Ministry of Science and ICT , South Korea (grant number: 2018R1C1B6009048 ) and was also supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) funded by the Ministry of Health & Welfare , South Korea (grant number: HI17C0929 ).

Funding Information:
This work was supported by the National Research Foundation of Korea grant funded by the Ministry of Science and ICT, South Korea (grant number: 2018R1C1B6009048) and was also supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) funded by the Ministry of Health & Welfare, South Korea (grant number: HI17C0929). The authors declare that there are no conflicts of interest.

Publisher Copyright:
© 2019 Elsevier Inc.

Keywords

Anti-proliferation
CCNE1
Cell cycle arrest
Endometriosis
Luteolin

ASJC Scopus subject areas

Endocrinology, Diabetes and Metabolism
Biochemistry
Molecular Biology
Nutrition and Dietetics
Clinical Biochemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.jnutbio.2019.02.006

Cite this

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title = "Ameliorative effects of luteolin against endometriosis progression in vitro and in vivo",

abstract = "Endometriosis is a common gynecological disease in reproductive-aged women. Generally, accumulation of backflow and debris of endometrial tissue develops into a lesion outside of the endometrium, inducing severe pelvic pain and infertility in some patients. Hormone therapy and surgery are the main treatments available, but various therapeutic phytochemicals are being reviewed in animal studies or clinical trials for endometriosis patients nowadays. However, the therapeutic effects of luteolin in human endometriosis have not been studied well. Here, we demonstrate that luteolin exerts antiproliferative and apoptotic effects in human VK2/E6E7 and End1/E6E7 and in an animal endometriosis model. Luteolin inhibits cell proliferation through cell cycle arrest and induces apoptosis through DNA fragmentation in VK2/E6E7 and End1/E6E7 cells. Cytosolic calcium levels, ROS production and lipid peroxidation also increased dose-dependently (0, 5, 10 and 20 μM) in the treatment with luteolin. In VK2/E6E7 and End1/E6E7 cells, luteolin decreased ERK1/2, JNK and PI3K/AKT signal proteins while activating P38. In addition, intraperitoneal injection of luteolin in the endometriosis mouse model reduced lesion size compared to vehicle-injected mice. Ccne1, Cdk2 and Cdk4 were significantly down-regulated in the autoimplanted endometriosis lesions of mice intraperitoneally injected with luteolin. Knockdown of CCNE1 mRNA in VK2/E6E7 and End1/E6E7 cells decreased cell viability through inhibition of G0/G1 phase progression and increased apoptosis. Together, our results imply that luteolin suppresses endometriosis development by regulation of the PI3K/AKT and MAPK signal proteins as well as the expression of CCNE1 in vitro and in vivo.",

keywords = "Anti-proliferation, CCNE1, Cell cycle arrest, Endometriosis, Luteolin",

author = "Sunwoo Park and Whasun Lim and Seungkwon You and Gwonhwa Song",

note = "Funding Information: This work was supported by the National Research Foundation of Korea grant funded by the Ministry of Science and ICT , South Korea (grant number: 2018R1C1B6009048 ) and was also supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) funded by the Ministry of Health & Welfare , South Korea (grant number: HI17C0929 ). Funding Information: This work was supported by the National Research Foundation of Korea grant funded by the Ministry of Science and ICT, South Korea (grant number: 2018R1C1B6009048) and was also supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) funded by the Ministry of Health & Welfare, South Korea (grant number: HI17C0929). The authors declare that there are no conflicts of interest. Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",

year = "2019",

month = may,

doi = "10.1016/j.jnutbio.2019.02.006",

language = "English",

volume = "67",

pages = "161--172",

journal = "Journal of Nutritional Biochemistry",

issn = "0955-2863",

publisher = "Elsevier Inc.",

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T1 - Ameliorative effects of luteolin against endometriosis progression in vitro and in vivo

AU - Park, Sunwoo

AU - Lim, Whasun

AU - You, Seungkwon

AU - Song, Gwonhwa

N1 - Funding Information: This work was supported by the National Research Foundation of Korea grant funded by the Ministry of Science and ICT , South Korea (grant number: 2018R1C1B6009048 ) and was also supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) funded by the Ministry of Health & Welfare , South Korea (grant number: HI17C0929 ). Funding Information: This work was supported by the National Research Foundation of Korea grant funded by the Ministry of Science and ICT, South Korea (grant number: 2018R1C1B6009048) and was also supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) funded by the Ministry of Health & Welfare, South Korea (grant number: HI17C0929). The authors declare that there are no conflicts of interest. Publisher Copyright: © 2019 Elsevier Inc.

PY - 2019/5

Y1 - 2019/5

N2 - Endometriosis is a common gynecological disease in reproductive-aged women. Generally, accumulation of backflow and debris of endometrial tissue develops into a lesion outside of the endometrium, inducing severe pelvic pain and infertility in some patients. Hormone therapy and surgery are the main treatments available, but various therapeutic phytochemicals are being reviewed in animal studies or clinical trials for endometriosis patients nowadays. However, the therapeutic effects of luteolin in human endometriosis have not been studied well. Here, we demonstrate that luteolin exerts antiproliferative and apoptotic effects in human VK2/E6E7 and End1/E6E7 and in an animal endometriosis model. Luteolin inhibits cell proliferation through cell cycle arrest and induces apoptosis through DNA fragmentation in VK2/E6E7 and End1/E6E7 cells. Cytosolic calcium levels, ROS production and lipid peroxidation also increased dose-dependently (0, 5, 10 and 20 μM) in the treatment with luteolin. In VK2/E6E7 and End1/E6E7 cells, luteolin decreased ERK1/2, JNK and PI3K/AKT signal proteins while activating P38. In addition, intraperitoneal injection of luteolin in the endometriosis mouse model reduced lesion size compared to vehicle-injected mice. Ccne1, Cdk2 and Cdk4 were significantly down-regulated in the autoimplanted endometriosis lesions of mice intraperitoneally injected with luteolin. Knockdown of CCNE1 mRNA in VK2/E6E7 and End1/E6E7 cells decreased cell viability through inhibition of G0/G1 phase progression and increased apoptosis. Together, our results imply that luteolin suppresses endometriosis development by regulation of the PI3K/AKT and MAPK signal proteins as well as the expression of CCNE1 in vitro and in vivo.

AB - Endometriosis is a common gynecological disease in reproductive-aged women. Generally, accumulation of backflow and debris of endometrial tissue develops into a lesion outside of the endometrium, inducing severe pelvic pain and infertility in some patients. Hormone therapy and surgery are the main treatments available, but various therapeutic phytochemicals are being reviewed in animal studies or clinical trials for endometriosis patients nowadays. However, the therapeutic effects of luteolin in human endometriosis have not been studied well. Here, we demonstrate that luteolin exerts antiproliferative and apoptotic effects in human VK2/E6E7 and End1/E6E7 and in an animal endometriosis model. Luteolin inhibits cell proliferation through cell cycle arrest and induces apoptosis through DNA fragmentation in VK2/E6E7 and End1/E6E7 cells. Cytosolic calcium levels, ROS production and lipid peroxidation also increased dose-dependently (0, 5, 10 and 20 μM) in the treatment with luteolin. In VK2/E6E7 and End1/E6E7 cells, luteolin decreased ERK1/2, JNK and PI3K/AKT signal proteins while activating P38. In addition, intraperitoneal injection of luteolin in the endometriosis mouse model reduced lesion size compared to vehicle-injected mice. Ccne1, Cdk2 and Cdk4 were significantly down-regulated in the autoimplanted endometriosis lesions of mice intraperitoneally injected with luteolin. Knockdown of CCNE1 mRNA in VK2/E6E7 and End1/E6E7 cells decreased cell viability through inhibition of G0/G1 phase progression and increased apoptosis. Together, our results imply that luteolin suppresses endometriosis development by regulation of the PI3K/AKT and MAPK signal proteins as well as the expression of CCNE1 in vitro and in vivo.

KW - Anti-proliferation

KW - CCNE1

KW - Cell cycle arrest

KW - Endometriosis

KW - Luteolin

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AN - SCOPUS:85063354001

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VL - 67

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ER -

Ameliorative effects of luteolin against endometriosis progression in vitro and in vivo

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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