Geldanamycin-Induced Osteosarcoma Cell Death Is Associated with Hyperacetylation and Loss of Mitochondrial Pool of Heat Shock Protein 60 (Hsp60)
Open Access
- 28 August 2013
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 8 (8), e71135
- https://doi.org/10.1371/journal.pone.0071135
Abstract
Osteosarcoma is one of the most malignant tumors of childhood and adolescence that is often resistant to standard chemo- and radio-therapy. Geldanamycin and geldanamycin analogs have been recently studied as potential anticancer agents for osteosarcoma treatment. Here, for the first time, we have presented novel anticancer mechanisms of geldanamycin biological activity. Moreover, we demonstrated an association between the effects of geldanamycin on the major heat shock proteins (HSPs) and the overall survival of highly metastatic human osteosarcoma 143B cells. We demonstrated that the treatment of 143B cells with geldanamycin caused a subsequent upregulation of cytoplasmic Hsp90 and Hsp70 whose activity is at least partly responsible for cancer development and drug resistance. On the other hand, geldanamycin induced upregulation of Hsp60 gene expression, and a simultaneous loss of hyperacetylated Hsp60 mitochondrial protein pool resulting in decreased viability and augmented cancer cell death. Hyperacetylation of Hsp60 seems to be associated with anticancer activity of geldanamycin. In light of the fact that mitochondrial dysfunction plays a critical role in the apoptotic signaling pathway, the presented data may support a hypothesis that Hsp60 can be another functional part of mitochondria-related acetylome being a potential target for developing novel anticancer strategies.Keywords
This publication has 43 references indexed in Scilit:
- Targeted inhibition of heat shock protein 90 disrupts multiple oncogenic signaling pathways, thus inducing cell cycle arrest and programmed cell death in human urinary bladder cancer cell linesCancer Cell International, 2013
- Proteomic Investigations of Lysine Acetylation Identify Diverse Substrates of Mitochondrial Deacetylase Sirt3PLOS ONE, 2012
- Hsp90 Molecular Chaperone Inhibitors: Are We There Yet?Clinical Cancer Research, 2012
- The Molecular Pathogenesis of Osteosarcoma: A ReviewSarcoma, 2011
- Benzoquinone ansamycin 17AAG binds to mitochondrial voltage-dependent anion channel and inhibits cell invasionProceedings of the National Academy of Sciences, 2011
- Cisplatin abrogates the geldanamycin-induced heat shock responseMolecular Cancer Therapeutics, 2008
- Therapy for OsteosarcomaPediatric Drugs, 2008
- Mammalian Sir2 Homolog SIRT3 Regulates Global Mitochondrial Lysine AcetylationMolecular and Cellular Biology, 2007
- Differential expression of Hsp90 isoforms in geldanamycin-treated 9L cellsBiochemical and Biophysical Research Communications, 2006
- Mitochondrial import of the human chaperonin (HSP60) proteinBiochemical and Biophysical Research Communications, 1990