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Phytomedicine, online 2 March 2025; Vol 140, May 2025, 156599 | https://doi.org/10.1016/j.phymed.2025.156599
β-Ionone suppresses colorectal tumorigenesis by activating OR51E2, a potential tumor suppressor
Ji-Sun Kim a#, Sungyun Cho a,b,c #, Mi-Young Jeong a, Adriana Rivera-Piza a, Yeonji Kim a, Chunyan Wu a, Ye Eun Yoon a, InRyeong Lee a, Jung-Won Choi a, Ha Lim Lee a, Sung Won Shin a, Jaeeun Shin a, Hyeonmin Gil d, Min-Goo Lee e, NaNa Keum f, Jin-A Kim g,h, Dain Lee h, Yong Hun Jung g, Seok Chung g,h, Min-Jeong Shin i,j, SungHoi Hong i,j, Sung-Gil Chi e, Sung-Joon Lee j,k
aDepartment of Biotechnology, Graduate school of Biotechnology, Korea University, Seoul 02841, South Korea
bDepartment of Pharmacology, Weill Cornell Medicine, Cornell University, New York, NY 10065, USA
cDepartment of Pharmacology, Korea University College of Medicine, Seoul 02841, South Korea
dDepartment of Life Science, Pohang University of Science and Technology (POSTECH), Pohang 37673, South Korea
eDepartment of Molecular Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, South Korea
fDepartment of Food Science and Biotechnology, Dongguk University, Gyeonggi 10325, South Korea
gSchool of Mechanical Engineering, Korea University, Seoul 02841, South Korea
hKU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, South Korea
iSchool of Biosystems and Biomedical Sciences, Korea University, Seoul 02841, South Korea
jInterdisciplinary Program in Precision Public Health, BK21 Four Institute of Precision Public Health, Korea University, Seoul 02841, South Korea
kDepartment of Food Bioscience & Technology, Korea University, Seoul 02841, South Korea
#These authors contributed equally to this work.
Corresponding author : Sung-Joon Lee
aDepartment of Biotechnology, Graduate school of Biotechnology, Korea University, Seoul 02841, South Korea
bDepartment of Pharmacology, Weill Cornell Medicine, Cornell University, New York, NY 10065, USA
cDepartment of Pharmacology, Korea University College of Medicine, Seoul 02841, South Korea
dDepartment of Life Science, Pohang University of Science and Technology (POSTECH), Pohang 37673, South Korea
eDepartment of Molecular Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, South Korea
fDepartment of Food Science and Biotechnology, Dongguk University, Gyeonggi 10325, South Korea
gSchool of Mechanical Engineering, Korea University, Seoul 02841, South Korea
hKU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, South Korea
iSchool of Biosystems and Biomedical Sciences, Korea University, Seoul 02841, South Korea
jInterdisciplinary Program in Precision Public Health, BK21 Four Institute of Precision Public Health, Korea University, Seoul 02841, South Korea
kDepartment of Food Bioscience & Technology, Korea University, Seoul 02841, South Korea
#These authors contributed equally to this work.
Corresponding author : Sung-Joon Lee
Abstract
Background
Olfactory receptors (ORs) are present in non-olfactory tissues and contribute to diverse biological roles beyond smell perception. Among them, OR51E2 has been associated with cancer biology, and its activator, β-ionone, a natural terpenoid, is known to have anticancer effects.
Purpose
This study aimed to clarify the tumor-suppressive role of OR51E2 in colorectal cancer (CRC), unravel the regulatory mechanism underlying its downregulation, and evaluate the therapeutic potential of β-ionone, an OR51E2 ligand, in CRC progression.
Study design and methods
OR51E2 expression was analyzed in human CRC tissues, matched adjacent normal tissues, and cell lines. The involvement of N6-methyladenosine (m6A) modification of OR51E2 mRNA stability was examined using METTL3/14 and YTHDF1/2/3 knockdown experiments. β-Ionone-mediated effects on intracellular calcium signaling, cell proliferation, migration, and apoptosis were evaluated in an OR51E2-dependent manner. The therapeutic efficacy of β-ionone was further evaluated in vivo using a xenograft model in nude mice.
Results
OR51E2 mRNA expression and immunoreactivity were significantly reduced in CRC cells and tissues due to decreased mRNA stability. Knockdown of METTL3/14 or YTHDF1/2/3 increased OR51E2 mRNA and protein expression and inhibited CRC cell proliferation. Treatment with STM2457, an METTL3 inhibitor, restored OR51E2 expression and suppressed CRC cell proliferation. β-Ionone, a ligand of OR51E2, increased intracellular calcium levels, decreased MEK/ERK phosphorylation, and inhibited CRC cell proliferation while inducing apoptosis. These effects were abolished in OR51E2 knockdown cells. In a xenograft model, β-ionone administration (5 and 10 mg/kg body weight) significantly reduced tumor growth.
Conclusion
This study identifies m6A modification as a critical mechanism underlying the downregulation of OR51E2 in CRC. Activation of OR51E2 by β-ionone suppresses CRC cell proliferation and induces apoptosis by elevating intracellular calcium levels, which inhibits the MEK-ERK pathway. These findings highlight OR51E2 as a potential therapeutic target and suggest that β-ionone or m6A inhibition may represent novel strategies for CRC treatment.
Olfactory receptors (ORs) are present in non-olfactory tissues and contribute to diverse biological roles beyond smell perception. Among them, OR51E2 has been associated with cancer biology, and its activator, β-ionone, a natural terpenoid, is known to have anticancer effects.
Purpose
This study aimed to clarify the tumor-suppressive role of OR51E2 in colorectal cancer (CRC), unravel the regulatory mechanism underlying its downregulation, and evaluate the therapeutic potential of β-ionone, an OR51E2 ligand, in CRC progression.
Study design and methods
OR51E2 expression was analyzed in human CRC tissues, matched adjacent normal tissues, and cell lines. The involvement of N6-methyladenosine (m6A) modification of OR51E2 mRNA stability was examined using METTL3/14 and YTHDF1/2/3 knockdown experiments. β-Ionone-mediated effects on intracellular calcium signaling, cell proliferation, migration, and apoptosis were evaluated in an OR51E2-dependent manner. The therapeutic efficacy of β-ionone was further evaluated in vivo using a xenograft model in nude mice.
Results
OR51E2 mRNA expression and immunoreactivity were significantly reduced in CRC cells and tissues due to decreased mRNA stability. Knockdown of METTL3/14 or YTHDF1/2/3 increased OR51E2 mRNA and protein expression and inhibited CRC cell proliferation. Treatment with STM2457, an METTL3 inhibitor, restored OR51E2 expression and suppressed CRC cell proliferation. β-Ionone, a ligand of OR51E2, increased intracellular calcium levels, decreased MEK/ERK phosphorylation, and inhibited CRC cell proliferation while inducing apoptosis. These effects were abolished in OR51E2 knockdown cells. In a xenograft model, β-ionone administration (5 and 10 mg/kg body weight) significantly reduced tumor growth.
Conclusion
This study identifies m6A modification as a critical mechanism underlying the downregulation of OR51E2 in CRC. Activation of OR51E2 by β-ionone suppresses CRC cell proliferation and induces apoptosis by elevating intracellular calcium levels, which inhibits the MEK-ERK pathway. These findings highlight OR51E2 as a potential therapeutic target and suggest that β-ionone or m6A inhibition may represent novel strategies for CRC treatment.
논문정보
- Research article
- 2025년 03월 (BRIC 등록일 2025-03-13)
- 국내(교신)+국외 연구진
- 생명과학 > 식품학
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