Cargando…

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

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Mu, Xiaodong, Isaac, Christian, Schott, Trevor, Huard, Johnny, Weiss, Kurt
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Hindawi Publishing Corporation 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3586506/
https://www.ncbi.nlm.nih.gov/pubmed/23476113
http://dx.doi.org/10.1155/2013/480713
_version_ 1782261314277605376
author Mu, Xiaodong
Isaac, Christian
Schott, Trevor
Huard, Johnny
Weiss, Kurt
author_facet Mu, Xiaodong
Isaac, Christian
Schott, Trevor
Huard, Johnny
Weiss, Kurt
author_sort Mu, Xiaodong
collection PubMed
description 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.
format Online
Article
Text
id pubmed-3586506
institution National Center for Biotechnology Information
language English
publishDate 2013
publisher Hindawi Publishing Corporation
record_format MEDLINE/PubMed
spelling pubmed-35865062013-03-09 Rapamycin Inhibits ALDH Activity, Resistance to Oxidative Stress, and Metastatic Potential in Murine Osteosarcoma Cells Mu, Xiaodong Isaac, Christian Schott, Trevor Huard, Johnny Weiss, Kurt Sarcoma Research Article 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. Hindawi Publishing Corporation 2013 2013-02-14 /pmc/articles/PMC3586506/ /pubmed/23476113 http://dx.doi.org/10.1155/2013/480713 Text en Copyright © 2013 Xiaodong Mu et al. https://creativecommons.org/licenses/by/3.0/ 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.
spellingShingle Research Article
Mu, Xiaodong
Isaac, Christian
Schott, Trevor
Huard, Johnny
Weiss, Kurt
Rapamycin Inhibits ALDH Activity, Resistance to Oxidative Stress, and Metastatic Potential in Murine Osteosarcoma Cells
title Rapamycin Inhibits ALDH Activity, Resistance to Oxidative Stress, and Metastatic Potential in Murine Osteosarcoma Cells
title_full Rapamycin Inhibits ALDH Activity, Resistance to Oxidative Stress, and Metastatic Potential in Murine Osteosarcoma Cells
title_fullStr Rapamycin Inhibits ALDH Activity, Resistance to Oxidative Stress, and Metastatic Potential in Murine Osteosarcoma Cells
title_full_unstemmed Rapamycin Inhibits ALDH Activity, Resistance to Oxidative Stress, and Metastatic Potential in Murine Osteosarcoma Cells
title_short Rapamycin Inhibits ALDH Activity, Resistance to Oxidative Stress, and Metastatic Potential in Murine Osteosarcoma Cells
title_sort rapamycin inhibits aldh activity, resistance to oxidative stress, and metastatic potential in murine osteosarcoma cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3586506/
https://www.ncbi.nlm.nih.gov/pubmed/23476113
http://dx.doi.org/10.1155/2013/480713
work_keys_str_mv AT muxiaodong rapamycininhibitsaldhactivityresistancetooxidativestressandmetastaticpotentialinmurineosteosarcomacells
AT isaacchristian rapamycininhibitsaldhactivityresistancetooxidativestressandmetastaticpotentialinmurineosteosarcomacells
AT schotttrevor rapamycininhibitsaldhactivityresistancetooxidativestressandmetastaticpotentialinmurineosteosarcomacells
AT huardjohnny rapamycininhibitsaldhactivityresistancetooxidativestressandmetastaticpotentialinmurineosteosarcomacells
AT weisskurt rapamycininhibitsaldhactivityresistancetooxidativestressandmetastaticpotentialinmurineosteosarcomacells