Inhibition of mitochondrial translation as a therapeutic strategy for human ovarian cancer to overcome chemoresistance
2019
Hu, Bo | Guo, Yue
Aberrant increase in mitochondrial biogenesis is common in human ovarian cancer and has great therapeutic value. In this work, we demonstrate that tigecycline, a FDA-approved broad spectrum antibiotic, selectively targets ovarian cancer cells through inhibition of mitochondrial translation. Tigecycline dose-dependently inhibits proliferation of ovarian cancer cells via arresting them at G2/M phase and induces apoptosis through caspase pathway. At the same concentration, tigecycline either does not or inhibits normal cells in a less extent than ovarian cancer cells. Mechanistically, tigecycline specifically inhibits translation by mitochondrial ribosome but not nuclear or cytosolic ribosome, leading to mitochondrial dysfunction, oxidative stress and damage, AMPK activation and inhibition of mTOR signaling in ovarian cancer cells. We further show that the inhibitory effects on ovarian cancer cell by tigecycline is mediated by its suppression of mitochondrial respiration. Importantly, the combination of tigecycline and cisplatin at sublethal concentration results in much greater efficacy than cisplatin alone in vitro and in vivo. Additionally, the effective dose of tigecycline in ovarian cancer is clinically achievable. Our study suggests that tigecycline is a useful addition to the treatment of ovarian cancer. Our work also highlights the targeted therapeutic potential of mitochondrial respiration in ovarian cancer.
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