Tumor Biology

, Volume 36, Issue 12, pp 9873–9883 | Cite as

Metformin inhibits the proliferation, metastasis, and cancer stem-like sphere formation in osteosarcoma MG63 cells in vitro

Research Article

Abstract

Metformin is an oral drug that has been widely used to treat type 2 diabetes mellitus. Interestingly, accumulated evidence indicate that metformin may reduce the risk of cancer in patients with type 2 diabetes and inhibit tumor cell growth and survival in numerous malignancies, including osteosarcoma (OS) cells. In the present study, we aimed to investigate the effects of metformin on the proliferation, migration, invasion, and sphere formation in OS MG63 cells in vitro. Metformin suppressed OS MG63 cell proliferation in a dose- and time-dependent manner and markedly blocked anti-metastatic potentials, migration, and invasion, by downregulating matrix metalloproteinase 2 (MMP2) and MMP9. Besides, we established OS cancer stem-like cell (CSC) model with sarcosphere formation assay and demonstrated that metformin posed damage on CSCs in OS by inhibiting sphere formation and by inducing their stemness loss. The stemness of CSCs in OS such as self-renewal and differentiation potentials was both impaired with a significant decrease of Oct-4 and Nanog activation. Consistent with this, the positive rates of CD90, CD133, and stage-specific embryonic antigen-4 (SSEA-4) were all observed with reductions in response to metformin exposure. In addition, Western blot showed that metformin activated AMPKα at Tyr172, followed by a downregulated phosphorylation of mammalian target of rapamycin (mTOR)/S6 and feedback activation of p-AKT Ser473 in both OS MG63 cells and CSCs. This indicates that AMPK/mTOR/S6 signaling pathway might be involved in the growth inhibition of both OS MG63 cells and CSCs. These results suggest that metformin, a potential anti-neoplastic agent, might make it a novel therapeutic choice for the treatment of OS in the future.

Keywords

Osteosarcoma Metformin Metastasis Cancer stem-like cells AMPK/mTOR/S6 signaling pathway 

Notes

Acknowledgments

The authors would like to thank Wu Zhang (Shanghai Institute of Hematology) for his technical assistance. This study was supported by grants from the Natural Sciences Foundation of China (no. 81172550).

Conflicts of interest

None

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  1. 1.Shanghai Key Laboratory for Prevention and Treatment of Bone and joint Diseases with Integrated Chinese-Western MedicineShanghai Institute of Orthopedics and TraumatologyShanghaiPeople’s Republic of China
  2. 2.Department of Orthopaedics, Ruijin Hospital, School of MedicineShanghai Jiaotong UniversityShanghaiPeople’s Republic of China
  3. 3.Wuxi Xinrui Hospital, Department of Orthopaedics, Wuxi Branch, Ruijin Hospital, School of MedicineShanghai Jiaotong UniversityWuxiPeople’s Republic of China

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