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Redox Biol. 2018 Oct;19:412-428. doi: 10.1016/j.redox.2018.09.009. Epub 2018 Sep 13.

Myostatin knockout induces apoptosis in human cervical cancer cells via elevated reactive oxygen species generation.

Author information

1
College of Animal Sciences and Veterinary Medicine, Henan Agricultural University, Zhengzhou, Henan Province, PR China.
2
College of Animal Sciences and Veterinary Medicine, Henan Agricultural University, Zhengzhou, Henan Province, PR China; Department of Radiology, University of Michigan, Ann Arbor, MI 48109-2200, USA.
3
Department of Endocrinology, the First Hospital of Lanzhou University, Lanzhou, Gansu Province, PR China.
4
Clinical Laboratory, the Second Hospital of Lanzhou University, Lanzhou, Gansu Province, PR China.
5
The Pathology Department of the Affiliated Cancer Hospital, Zhengzhou University, Zhengzhou, Henan Province, PR China.
6
College of Animal Sciences and Veterinary Medicine, Henan Agricultural University, Zhengzhou, Henan Province, PR China. Electronic address: haubiochem@163.com.
7
College of Animal Sciences and Veterinary Medicine, Henan Agricultural University, Zhengzhou, Henan Province, PR China. Electronic address: wangjiang_hau@126.com.
8
College of Animal Sciences and Veterinary Medicine, Henan Agricultural University, Zhengzhou, Henan Province, PR China. Electronic address: chubeibei_hau@hotmail.com.

Abstract

Myostatin (Mstn) is postulated to be a key determinant of muscle loss and cachexia in cancer. However, no experimental evidence supports a role for Mstn in cancer, particularly in regulating the survival and growth of cancer cells. In this study, we showed that the expression of Mstn was significantly increased in different tumor tissues and human cancer cells. Mstn knockdown inhibited the proliferation of cancer cells. A knockout (KO) of Mstn created by clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein (Cas) 9 (CRISPR/Cas9) induced mitochondria-dependent apoptosis in HeLa cells. Furthermore, KO of Mstn reduced the lipid content. Molecular analyses demonstrated that the expression levels of fatty acid oxidation-related genes were upregulated and then increased rate of fatty acid oxidation. Mstn deficiency-induced apoptosis took place along with generation of reactive oxygen species (ROS) and elevated fatty acid oxidation, which may play a role in triggering mitochondrial membrane depolarization, the release of cytochrome c (Cyt-c), and caspase activation. Importantly, apoptosis induced by Mstn KO was partially rescued by antioxidants and etomoxir, thereby suggesting that the increased level of ROS was functionally involved in mediating apoptosis. Overall, our findings demonstrate a novel function of Mstn in regulating mitochondrial metabolism and apoptosis within cancer cells. Hence, inhibiting the production and function of Mstn may be an effective therapeutic intervention during cancer progression and muscle loss in cachexia.

KEYWORDS:

Apoptosis; CRISPR/Cas9; Myostatin; Reactive oxygen species

PMID:
30241032
PMCID:
PMC6146590
DOI:
10.1016/j.redox.2018.09.009
[Indexed for MEDLINE]
Free PMC Article

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