About this Journal Submit a Manuscript Table of Contents
Sarcoma
Volume 2013 (2013), Article ID 480713, 11 pages
http://dx.doi.org/10.1155/2013/480713
Research Article

Rapamycin Inhibits ALDH Activity, Resistance to Oxidative Stress, and Metastatic Potential in Murine Osteosarcoma Cells

1Stem Cell Research Center, University of Pittsburgh School of Medicine, Bridgeside Point II, 450 Technology Drive, Pittsburgh, PA 15219, USA
2Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Bridgeside Point II, 450 Technology Drive, Pittsburgh, PA 15219, USA

Received 13 September 2012; Revised 4 December 2012; Accepted 22 December 2012

Academic Editor: Norman Jaffe

Copyright © 2013 Xiaodong Mu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Osteosarcoma (OS) is the most common primary malignancy of bone. Mortality is determined by the presence of metastatic disease, but little is known regarding the biochemical events that drive metastases. Two murine OS cell lines, K7M2 and K12, are related but differ significantly in their metastatic potentials: K7M2 is highly metastatic whereas K12 displays much less metastatic potential. Using this experimental system, the mammalian target of rapamycin (mTOR) pathway has been implicated in OS metastasis. We also discovered that aldehyde dehydrogenase (ALDH, a stem cell marker) activity is higher in K7M2 cells than K12 cells. Rapamycin treatment reduces the expression and enzymatic activity of ALDH in K7M2 cells. ALDH inhibition renders these cells more susceptible to apoptotic death when exposed to oxidative stress. Furthermore, rapamycin treatment reduces bone morphogenetic protein-2 (BMP2) and vascular endothelial growth factor (VEGF) gene expression and inhibits K7M2 proliferation, migration, and invasion in vitro. Inhibition of ALDH with disulfiram correlated with decreased mTOR expression and activity. In conclusion, we provide evidence for interaction between mTOR activity, ALDH activity, and metastatic potential in murine OS cells. Our work suggests that mTOR and ALDH are therapeutic targets for the treatment and prevention of OS metastasis.