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Metformin Suppresses Self-Renewal Ability and Tumorigenicity of Osteosarcoma Stem Cells via Reactive Oxygen Species-Mediated Apoptosis and Autophagy.
- Source :
-
Oxidative medicine and cellular longevity [Oxid Med Cell Longev] 2019 Nov 18; Vol. 2019, pp. 9290728. Date of Electronic Publication: 2019 Nov 18 (Print Publication: 2019). - Publication Year :
- 2019
-
Abstract
- Osteosarcoma is the most frequently diagnosed primary malignant bone sarcoma in children and adolescents. Recent studies have shown that cancer stem cells (CSCs), a cluster of tumor cells with the ability to self-renew, play an essential role in tumor recurrence and metastasis. Thus, it is necessary to develop therapeutic strategies specifically targeting CSCs. Metformin, the first-line drug for type 2 diabetes, exhibits antineoplastic activities in various kinds of tumors. New evidence has suggested that metformin may target CSCs and prevent their recurrence. However, the underlying specific mechanisms remain unclear. In this study, we found that metformin significantly suppressed the self-renewal ability of osteosarcoma stem cells (OSCs) and induced G0/G1 phase arrest by blocking the activity of cyclin-dependent kinases. Furthermore, metformin induced apoptosis through a mitochondria-dependent pathway, leading to the collapse of the mitochondrial transmembrane potential and the production of reactive oxygen species (ROS). Importantly, metformin acted directly on the mitochondria, which resulted in decreased ATP synthesis. This change allowed access to the downstream AMPK kinase, and the activation of AMPK led to the reversal of the mTOR pathway, triggering autophagy. Particularly, metformin-mediated autophagy disturbed the homeostasis of stemness and pluripotency in the OSCs. Additionally, our mouse xenograft model confirmed the potential therapeutic use of metformin in targeting OSCs. In conclusion, our findings suggest that metformin suppresses the self-renewal ability and tumorigenicity of OSCs via ROS-mediated apoptosis and autophagy.<br />Competing Interests: The authors declare that they have no conflict of interest.<br /> (Copyright © 2019 Bin Zhao et al.)
- Subjects :
- Animals
Bone Neoplasms drug therapy
Bone Neoplasms metabolism
Bone Neoplasms pathology
Cell Cycle drug effects
Cell Proliferation drug effects
Humans
Hypoglycemic Agents pharmacology
Male
Membrane Potential, Mitochondrial drug effects
Mice
Mice, Inbred BALB C
Neoplastic Stem Cells drug effects
Neoplastic Stem Cells metabolism
Neoplastic Stem Cells pathology
Osteosarcoma metabolism
Osteosarcoma pathology
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
Antineoplastic Agents pharmacology
Apoptosis drug effects
Autophagy
Cell Self Renewal drug effects
Metformin pharmacology
Osteosarcoma drug therapy
Reactive Oxygen Species metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1942-0994
- Volume :
- 2019
- Database :
- MEDLINE
- Journal :
- Oxidative medicine and cellular longevity
- Publication Type :
- Academic Journal
- Accession number :
- 31827709
- Full Text :
- https://doi.org/10.1155/2019/9290728