원미선 (한국생명공학연구원, 원큐어젠)

한빛사논문

조회299

한국생명공학연구원, 원큐어젠

Exp. Mol. Med., Jan 22 2024, | https://doi.org/10.1038/s12276-024-01155-9 CYB5R3 functions as a tumor suppressor by inducing ER stress-mediated apoptosis in lung cancer cells via the PERK-ATF4 and IRE1α-JNK pathways

Joo-Young Im ^{1 *}, Soo Jin Kim ², Jong-Lyul Park ^{3 4}, Tae-Hee Han^{5 6}, Woo-Il Kim ³, Inhyub Kim ³, Bomin Ko ³, So-Young Chun ³, Mi-Jung Kang³, Bo-Kyung Kim ^{3 7}, Sol A Jeon ³, Seon-Kyu Kim ^{3 4}, Incheol Ryu ⁸, Seon-Young Kim ^{3 6}, Ki-Hoan Nam ⁹, Inah Hwang ¹⁰, Hyun Seung Ban ^{5 6}, Misun Won ^{11 12 13 *}

¹Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea.

²Chungnam National University Sejong Hospital (CNUSH), Sejong, 30099, Republic of Korea.

³Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea.

⁴Aging Convergence Research Center, KRIBB, Daejeon, 34141, Republic of Korea.

⁵Biotherapeutics Translational Research Center, KRIBB, Daejeon, 34141, Republic of Korea.

⁶KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon, 34113, Republic of Korea.

⁷R&D Center, OneCureGEN Co., Ltd., Daejeon, 34141, Republic of Korea.

⁸YD Global Life Science Co., Ltd., Seongnam-si, Gyeonggi-do, 13207, Republic of Korea.

⁹Laboratory Animal Resource & Research Center, KRIBB, Cheongju, Chungbuk, Republic of Korea.

¹⁰Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, 03760, Republic of Korea.

¹¹Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea.

¹²KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon, 34113, Republic of Korea.

¹³R&D Center, OneCureGEN Co., Ltd., Daejeon, 34141, Republic of Korea.

^*Corresponding authors: correspondence to Joo-Young Im or Misun Won

Abstract

Cytochrome b5 reductase 3 (CYB5R3) is involved in various cellular metabolic processes, including fatty acid synthesis and drug metabolism. However, the role of CYB5R3 in cancer development remains poorly understood. Here, we show that CYB5R3 expression is downregulated in human lung cancer cell lines and tissues. Adenoviral overexpression of CYB5R3 suppresses lung cancer cell growth in vitro and in vivo. However, CYB5R3 deficiency promotes tumorigenesis and metastasis in mouse models. Transcriptome analysis revealed that apoptosis- and endoplasmic reticulum (ER) stress-related genes are upregulated in CYB5R3-overexpressing lung cancer cells. Metabolomic analysis revealed that CYB5R3 overexpression increased the production of nicotinamide adenine dinucleotide (NAD⁺) and oxidized glutathione (GSSG). Ectopic CYB5R3 is mainly localized in the ER, where CYB5R3-dependent ER stress signaling is induced via activation of protein kinase RNA-like ER kinase (PERK) and inositol-requiring enzyme 1 alpha (IRE1α). Moreover, NAD⁺ activates poly (ADP-ribose) polymerase16 (PARP16), an ER-resident protein, to promote ADP-ribosylation of PERK and IRE1α and induce ER stress. In addition, CYB5R3 induces the generation of reactive oxygen species and caspase-9-dependent intrinsic cell death. Our findings highlight the importance of CYB5R3 as a tumor suppressor for the development of CYB5R3-based therapeutics for lung cancer.

논문정보

형식Research article
게재일2024년 01월 (BRIC 등록일 2024-01-23)
연구진국내 연구진
분야 생명과학 > 분자생물학

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