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

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.

• Authors: Ying-Qian Han, Sheng-Li Ming, Hong-Tao Wu, Lei Zeng, Gen Ba, Jian Li, Wei-Fei Lu, Jie Han, Qia-Jun Du, Miao-Miao Sun, Guo-Yu Yang, Jiang Wang, Bei-Bei Chu
• Journal: Redox biology (Redox Biol) Vol. 19 Pg. 412-428 (10 2018) ISSN: 2213-2317 [Electronic] Netherlands
• PMID: 30241032 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• Antioxidants
• Epoxy Compounds
• Fatty Acids
• MSTN protein, human
• Myostatin
• Reactive Oxygen Species
• Cytochromes c
• Caspases
• etomoxir

Topics

• A549 Cells
• Animals
• Antioxidants (pharmacology)
• Apoptosis (genetics)
• CRISPR-Cas Systems (genetics)
• Cachexia (pathology)
• Caspases (metabolism)
• Cell Line, Tumor
• Cell Proliferation (genetics)
• Clustered Regularly Interspaced Short Palindromic Repeats (genetics)
• Cytochromes c (metabolism)
• Epoxy Compounds (pharmacology)
• Fatty Acids (metabolism)
• Female
• Gene Knockout Techniques
• HEK293 Cells
• HeLa Cells
• Humans
• Lipid Metabolism (physiology)
• Membrane Potential, Mitochondrial (genetics)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Mitochondria (genetics, metabolism)
• Myostatin (genetics)
• Oxidation-Reduction
• Reactive Oxygen Species (metabolism)
• Uterine Cervical Neoplasms (genetics, pathology)
• Xenograft Model Antitumor Assays