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线粒体衍生肽 MOTS-c 通过减弱 USP7 介导的 LARS1 去泛素化抑制卵巢癌进展。

Mitochondrial-Derived Peptide MOTS-c Suppresses Ovarian Cancer Progression by Attenuating USP7-Mediated LARS1 Deubiquitination.

机构信息

Department of Gynaecology and Obstetrics, Xijing Hospital, Air Force Medical University, Xi'an, 710032, China.

Department of Traditional Chinese Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.

出版信息

Adv Sci (Weinh). 2024 Nov;11(43):e2405620. doi: 10.1002/advs.202405620. Epub 2024 Sep 25.

DOI:10.1002/advs.202405620
PMID:39321430
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11578304/
Abstract

Mitochondrial-nuclear communication plays a vital role in maintaining cellular homeostasis. MOTS-c, a short peptide derived from the 12S rRNA of mitochondrial DNA, has been suggested as a retrograde mitochondrial signal. Although recent clinical studies have suggested a possible link between MOTS-c and human cancer, the role of MOTS-c in tumorigenesis has yet to be investigated. Here, MOTS-c levels are found to be reduced in both serum and tumor tissues from ovarian cancer (OC) patients, which are associated with poor patients' prognosis. Exogenous MOTS-c inhibits the proliferation, migration and invasion of OC cells, and induces cell cycle arrest and apoptosis. Mechanistically, MOTS-c interacts with LARS1 and promotes its ubiquitination and proteasomal degradation. In addition, USP7 was identified as a deubiquitinase of LARS1, and MOTS-c can attenuates USP7-mediated LARS1 deubiquitination by competing with USP7 for binding to LARS1. Besides, LARS1 was found to be increased and play an important oncogenic function in OC. More importantly, MOTS-c displays a marked anti-tumor effect on OC growth without systemic toxicity in vivo. In conclusion, this study reveals a crucial role of MOTS-c in OC and provides a possibility for MOTS-c as a therapeutic target for the treatment of this manlignacy.

摘要

线粒体-核通讯在维持细胞内稳态中起着至关重要的作用。MOTS-c 是一种源自线粒体 DNA 12S rRNA 的短肽，被认为是一种逆行线粒体信号。尽管最近的临床研究表明 MOTS-c 与人类癌症之间可能存在联系，但 MOTS-c 在肿瘤发生中的作用尚未得到研究。在这里，我们发现卵巢癌（OC）患者的血清和肿瘤组织中 MOTS-c 水平降低，这与患者预后不良有关。外源性 MOTS-c 抑制 OC 细胞的增殖、迁移和侵袭，并诱导细胞周期停滞和细胞凋亡。在机制上，MOTS-c 与 LARS1 相互作用，并促进其泛素化和蛋白酶体降解。此外，USP7 被鉴定为 LARS1 的去泛素酶，MOTS-c 可以通过与 USP7 竞争结合 LARS1 来减弱 USP7 介导的 LARS1 去泛素化。此外，LARS1 在 OC 中被发现增加并发挥重要的致癌作用。更重要的是，MOTS-c 在体内对 OC 生长表现出显著的抗肿瘤作用，而没有全身毒性。总之，本研究揭示了 MOTS-c 在 OC 中的关键作用，并为 MOTS-c 作为治疗这种恶性肿瘤的治疗靶点提供了可能性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6eb/11578304/f544fbf07184/ADVS-11-2405620-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6eb/11578304/6fce2870adc7/ADVS-11-2405620-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6eb/11578304/a1f97958ad8e/ADVS-11-2405620-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6eb/11578304/c81000868be8/ADVS-11-2405620-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6eb/11578304/1115216176c7/ADVS-11-2405620-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6eb/11578304/395c925bd705/ADVS-11-2405620-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6eb/11578304/face61a4289f/ADVS-11-2405620-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6eb/11578304/f4b686117231/ADVS-11-2405620-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6eb/11578304/fdb666ec38a4/ADVS-11-2405620-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6eb/11578304/f544fbf07184/ADVS-11-2405620-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6eb/11578304/6fce2870adc7/ADVS-11-2405620-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6eb/11578304/a1f97958ad8e/ADVS-11-2405620-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6eb/11578304/c81000868be8/ADVS-11-2405620-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6eb/11578304/1115216176c7/ADVS-11-2405620-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6eb/11578304/395c925bd705/ADVS-11-2405620-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6eb/11578304/face61a4289f/ADVS-11-2405620-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6eb/11578304/f4b686117231/ADVS-11-2405620-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6eb/11578304/fdb666ec38a4/ADVS-11-2405620-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6eb/11578304/f544fbf07184/ADVS-11-2405620-g007.jpg

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