The tumor suppressive role of TIMP3 in the human osteosarcoma cells.

Abstract

Tissue inhibitor of metalloproteinase 3 (TIMP3) regulates a variety of cellular activities such as proliferation, viability, apoptosis, and motility. Functional loss of TIMP3 is reported in several human cancers. However, its role in osteosarcoma (OS) remains largely unclear. In this study, we explored the mechanism underlying the modulation of TIMP3 in the growth and aggressiveness of U2OS and 143B human OS cells at both cellular and molecular levels. Our results show that overexpression of TIMP3 inhibits endogenous MMP activity and represses a series of oncogenic phenotypes of tumor cells independent of MMP inhibition, including reduced proliferation and survival, induced apoptosis, as well as improved sensitivity of tumor cells in response to cisplatin chemotherapy. TIMP3 overexpression also suppresses tumor cell invasion via its MMP inhibitory capacity. Importantly, TIMP3 modulates tumor cell oncogenesis via its induction of PTEN and subsequent inactivation of the PI3K/AKT pathway. Our results suggest that TIMP3 is an oncosuppressor in human OS cells. Reactivation of TIMP3 function may be considered as a potential therapy for the treatment of this bone cancer.