Estrogen receptor beta-mediated modulation of lung cancer cell proliferation by 27-hydroxycholesterol

Shiro Hiramitsu, Tomonori Ishikawa, Wan Ru Lee, Tamor Khan, Christine Crumbley, Nimra Khwaja, Faezeh Zamanian, Arvand Asghari, Mehmet Sen, Yang Zhang, John R. Hawse, John D. Minna, Michihisa Umetani

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

27-hydroxycholesterol (27HC) is an abundant cholesterol metabolite in human circulation and promotes breast cancer cell proliferation. Although lung is one of the organs that contain high levels of 27HC, the role of 27HC in lung is unknown. In this study, we found that 27HC promotes lung cancer cell proliferation in an estrogen receptor β (ERβ)-dependent manner. The expression of 27HC-generating enzyme CYP27A1 is higher in lung cancer cells than in normal lung cells. Treatment with 27HC increased cell proliferation in ERβ-positive lung cancer cells, but not in ERα-positive or ER-negative cells. The effect on cell proliferation is specific to 27HC and another oxysterol, 25-hydroxycholesterol that has a similar oxysterol structure with 27HC. Moreover, among ligands for nuclear receptors tested, only estrogen had the proliferative effect, and the effect by 27HC and estrogen was inhibited by ERβ-specific, but not ERα-specific, inhibitors. In addition, the effect by 27HC was not affected by membrane-bound estrogen receptor GPR30. Interestingly, despite the high expression of CYP27A1, endogenously produced 27HC was not the major contributor of the 27HC-induced cell proliferation. Using kinase inhibitors, we found that the effect by 27HC was mediated by the PI3K-Akt signaling pathway. These results suggest that 27HC promotes lung cancer cell proliferation via ERβ and PI3K-Akt signaling. Thus, lowering 27HC levels may lead to a novel approach for the treatment of lung cancer.

Original languageEnglish (US)
Article number470
JournalFrontiers in Endocrinology
Volume9
Issue numberAUG
DOIs
StatePublished - Aug 23 2018

Fingerprint

Estrogen Receptor beta
Lung Neoplasms
Cell Proliferation
Estrogen Receptors
27-hydroxycholesterol
Phosphatidylinositol 3-Kinases
Lung
Estrogens
Cytoplasmic and Nuclear Receptors

Keywords

  • 27-hydroxycholesterol
  • Cholesterol metabolites
  • ERβ
  • Estrogen receptor
  • Lung cancer

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism

Cite this

Hiramitsu, S., Ishikawa, T., Lee, W. R., Khan, T., Crumbley, C., Khwaja, N., ... Umetani, M. (2018). Estrogen receptor beta-mediated modulation of lung cancer cell proliferation by 27-hydroxycholesterol. Frontiers in Endocrinology, 9(AUG), [470]. https://doi.org/10.3389/fendo.2018.00470

Estrogen receptor beta-mediated modulation of lung cancer cell proliferation by 27-hydroxycholesterol. / Hiramitsu, Shiro; Ishikawa, Tomonori; Lee, Wan Ru; Khan, Tamor; Crumbley, Christine; Khwaja, Nimra; Zamanian, Faezeh; Asghari, Arvand; Sen, Mehmet; Zhang, Yang; Hawse, John R.; Minna, John D.; Umetani, Michihisa.

In: Frontiers in Endocrinology, Vol. 9, No. AUG, 470, 23.08.2018.

Research output: Contribution to journalArticle

Hiramitsu, S, Ishikawa, T, Lee, WR, Khan, T, Crumbley, C, Khwaja, N, Zamanian, F, Asghari, A, Sen, M, Zhang, Y, Hawse, JR, Minna, JD & Umetani, M 2018, 'Estrogen receptor beta-mediated modulation of lung cancer cell proliferation by 27-hydroxycholesterol', Frontiers in Endocrinology, vol. 9, no. AUG, 470. https://doi.org/10.3389/fendo.2018.00470
Hiramitsu, Shiro ; Ishikawa, Tomonori ; Lee, Wan Ru ; Khan, Tamor ; Crumbley, Christine ; Khwaja, Nimra ; Zamanian, Faezeh ; Asghari, Arvand ; Sen, Mehmet ; Zhang, Yang ; Hawse, John R. ; Minna, John D. ; Umetani, Michihisa. / Estrogen receptor beta-mediated modulation of lung cancer cell proliferation by 27-hydroxycholesterol. In: Frontiers in Endocrinology. 2018 ; Vol. 9, No. AUG.
@article{65c1f03e69ef48bfafdeba15a316562a,
title = "Estrogen receptor beta-mediated modulation of lung cancer cell proliferation by 27-hydroxycholesterol",
abstract = "27-hydroxycholesterol (27HC) is an abundant cholesterol metabolite in human circulation and promotes breast cancer cell proliferation. Although lung is one of the organs that contain high levels of 27HC, the role of 27HC in lung is unknown. In this study, we found that 27HC promotes lung cancer cell proliferation in an estrogen receptor β (ERβ)-dependent manner. The expression of 27HC-generating enzyme CYP27A1 is higher in lung cancer cells than in normal lung cells. Treatment with 27HC increased cell proliferation in ERβ-positive lung cancer cells, but not in ERα-positive or ER-negative cells. The effect on cell proliferation is specific to 27HC and another oxysterol, 25-hydroxycholesterol that has a similar oxysterol structure with 27HC. Moreover, among ligands for nuclear receptors tested, only estrogen had the proliferative effect, and the effect by 27HC and estrogen was inhibited by ERβ-specific, but not ERα-specific, inhibitors. In addition, the effect by 27HC was not affected by membrane-bound estrogen receptor GPR30. Interestingly, despite the high expression of CYP27A1, endogenously produced 27HC was not the major contributor of the 27HC-induced cell proliferation. Using kinase inhibitors, we found that the effect by 27HC was mediated by the PI3K-Akt signaling pathway. These results suggest that 27HC promotes lung cancer cell proliferation via ERβ and PI3K-Akt signaling. Thus, lowering 27HC levels may lead to a novel approach for the treatment of lung cancer.",
keywords = "27-hydroxycholesterol, Cholesterol metabolites, ERβ, Estrogen receptor, Lung cancer",
author = "Shiro Hiramitsu and Tomonori Ishikawa and Lee, {Wan Ru} and Tamor Khan and Christine Crumbley and Nimra Khwaja and Faezeh Zamanian and Arvand Asghari and Mehmet Sen and Yang Zhang and Hawse, {John R.} and Minna, {John D.} and Michihisa Umetani",
year = "2018",
month = "8",
day = "23",
doi = "10.3389/fendo.2018.00470",
language = "English (US)",
volume = "9",
journal = "Frontiers in Endocrinology",
issn = "1664-2392",
publisher = "Frontiers Media S. A.",
number = "AUG",

}

TY - JOUR

T1 - Estrogen receptor beta-mediated modulation of lung cancer cell proliferation by 27-hydroxycholesterol

AU - Hiramitsu, Shiro

AU - Ishikawa, Tomonori

AU - Lee, Wan Ru

AU - Khan, Tamor

AU - Crumbley, Christine

AU - Khwaja, Nimra

AU - Zamanian, Faezeh

AU - Asghari, Arvand

AU - Sen, Mehmet

AU - Zhang, Yang

AU - Hawse, John R.

AU - Minna, John D.

AU - Umetani, Michihisa

PY - 2018/8/23

Y1 - 2018/8/23

N2 - 27-hydroxycholesterol (27HC) is an abundant cholesterol metabolite in human circulation and promotes breast cancer cell proliferation. Although lung is one of the organs that contain high levels of 27HC, the role of 27HC in lung is unknown. In this study, we found that 27HC promotes lung cancer cell proliferation in an estrogen receptor β (ERβ)-dependent manner. The expression of 27HC-generating enzyme CYP27A1 is higher in lung cancer cells than in normal lung cells. Treatment with 27HC increased cell proliferation in ERβ-positive lung cancer cells, but not in ERα-positive or ER-negative cells. The effect on cell proliferation is specific to 27HC and another oxysterol, 25-hydroxycholesterol that has a similar oxysterol structure with 27HC. Moreover, among ligands for nuclear receptors tested, only estrogen had the proliferative effect, and the effect by 27HC and estrogen was inhibited by ERβ-specific, but not ERα-specific, inhibitors. In addition, the effect by 27HC was not affected by membrane-bound estrogen receptor GPR30. Interestingly, despite the high expression of CYP27A1, endogenously produced 27HC was not the major contributor of the 27HC-induced cell proliferation. Using kinase inhibitors, we found that the effect by 27HC was mediated by the PI3K-Akt signaling pathway. These results suggest that 27HC promotes lung cancer cell proliferation via ERβ and PI3K-Akt signaling. Thus, lowering 27HC levels may lead to a novel approach for the treatment of lung cancer.

AB - 27-hydroxycholesterol (27HC) is an abundant cholesterol metabolite in human circulation and promotes breast cancer cell proliferation. Although lung is one of the organs that contain high levels of 27HC, the role of 27HC in lung is unknown. In this study, we found that 27HC promotes lung cancer cell proliferation in an estrogen receptor β (ERβ)-dependent manner. The expression of 27HC-generating enzyme CYP27A1 is higher in lung cancer cells than in normal lung cells. Treatment with 27HC increased cell proliferation in ERβ-positive lung cancer cells, but not in ERα-positive or ER-negative cells. The effect on cell proliferation is specific to 27HC and another oxysterol, 25-hydroxycholesterol that has a similar oxysterol structure with 27HC. Moreover, among ligands for nuclear receptors tested, only estrogen had the proliferative effect, and the effect by 27HC and estrogen was inhibited by ERβ-specific, but not ERα-specific, inhibitors. In addition, the effect by 27HC was not affected by membrane-bound estrogen receptor GPR30. Interestingly, despite the high expression of CYP27A1, endogenously produced 27HC was not the major contributor of the 27HC-induced cell proliferation. Using kinase inhibitors, we found that the effect by 27HC was mediated by the PI3K-Akt signaling pathway. These results suggest that 27HC promotes lung cancer cell proliferation via ERβ and PI3K-Akt signaling. Thus, lowering 27HC levels may lead to a novel approach for the treatment of lung cancer.

KW - 27-hydroxycholesterol

KW - Cholesterol metabolites

KW - ERβ

KW - Estrogen receptor

KW - Lung cancer

UR - http://www.scopus.com/inward/record.url?scp=85052195727&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85052195727&partnerID=8YFLogxK

U2 - 10.3389/fendo.2018.00470

DO - 10.3389/fendo.2018.00470

M3 - Article

VL - 9

JO - Frontiers in Endocrinology

JF - Frontiers in Endocrinology

SN - 1664-2392

IS - AUG

M1 - 470

ER -