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

Xiaodong Mu1, Christian Isaac, Trevor Schott

  • 1Stem Cell Research Center, University of Pittsburgh School of Medicine, Bridgeside Point II, 450 Technology Drive, Pittsburgh, PA 15219, USA.

Sarcoma
|March 12, 2013
PubMed

Insights

This study implicates the mammalian target of rapamycin (mTOR) pathway and aldehyde dehydrogenase (ALDH) activity in osteosarcoma (OS) metastasis. Targeting mTOR and ALDH may offer new therapeutic strategies for preventing OS spread.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Osteosarcoma (OS) is the most common primary bone cancer.
  • Metastasis significantly impacts patient mortality in OS.
  • Biochemical drivers of OS metastasis are not well understood.

Purpose of the Study:

  • To investigate the role of the mammalian target of rapamycin (mTOR) pathway in OS metastasis.
  • To explore the relationship between aldehyde dehydrogenase (ALDH) activity and metastatic potential in OS.
  • To identify potential therapeutic targets for OS metastasis.

Main Methods:

  • Utilized two murine OS cell lines (K7M2 and K12) with differing metastatic potentials.
  • Administered rapamycin to assess its effects on ALDH activity, gene expression (BMP2, VEGF), and cellular functions (proliferation, migration, invasion).
  • Investigated the impact of ALDH inhibition using disulfiram on mTOR signaling.

Main Results:

  • mTOR pathway activity is linked to OS metastasis.
  • Higher ALDH activity (a stem cell marker) observed in highly metastatic K7M2 cells.
  • Rapamycin reduced ALDH expression/activity, sensitized cells to oxidative stress-induced apoptosis, and decreased expression of BMP2 and VEGF.
  • Disulfiram inhibition of ALDH correlated with reduced mTOR expression and activity.
  • Rapamycin treatment inhibited K7M2 proliferation, migration, and invasion in vitro.

Conclusions:

  • Evidence suggests an interaction between mTOR activity, ALDH activity, and metastatic potential in murine OS cells.
  • mTOR and ALDH are potential therapeutic targets for treating and preventing OS metastasis.

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