조성윤 (고려대학교 의과대학, Cornell University) | 한빛사논문 > 한빛사

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조회71

고려대학교 의과대학, Cornell University

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Phytomedicine, 2 March 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,b,1, Sungyun Cho ^a,c,1, 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 ^d,f, Jin-A Kim ^g,h, Dain Lee ^h, Yong Hun Jung ^g, Seok Chung ^g,h, Min-Jeong Shin ^b,i, SungHoi Hong ^b,i, Sung-Gil Chi ^e, Sung-Joon Lee^b,j

^aDepartment of Biotechnology, Graduate school of Biotechnology, Korea University, Seoul 02841, South Korea
^bBK21 FOUR Institute of Precision Public Health, Interdisciplinary Program in Precision Public Health, Korea University, Seoul 02855, South Korea
^cDepartment of Pharmacology, Weill Cornell Medicine, Cornell University, New York, NY 14853, USA
^dDepartment of Food Science and Biotechnology, Dongguk University, Gyeonggi 10325, South Korea
^eDepartment of Molecular Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul 02838, South Korea
^fDepartment of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA 02138, USA
^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
^jDepartment of Food Bioscience & Technology, Korea University, Seoul 02841, South Korea

¹These authors contributed equally to this work.
Correspondence to Sung-Joon Lee, Professor

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.

논문정보

형식Research article
게재일2025년 03월 (BRIC 등록일 2025-03-13)
연구진국내(교신)+국외 연구진
분야 생명과학 > 식품학

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