Geldanamycin-induced osteosarcoma cell death is associated with hyperacetylation and loss of mitochondrial pool of heat shock protein 60 (hsp60)

Magdalena Gorska; Antonella Marino Gammazza; Michal Aleksander Zmijewski; Claudia Campanella; Francesco Cappello; Tomasz Wasiewicz; Alicja Kuban-Jankowska; Agnieszka Daca; Alicja Sielicka; Urszula Popowska; Narcyz Knap; Jakub Antoniewicz; Takashi Wakabayashi; Michal Wozniak

doi:10.1371/journal.pone.0071135

Geldanamycin-induced osteosarcoma cell death is associated with hyperacetylation and loss of mitochondrial pool of heat shock protein 60 (hsp60)

PLoS One. 2013 Aug 28;8(8):e71135. doi: 10.1371/journal.pone.0071135. eCollection 2013.

Authors

Magdalena Gorska¹, Antonella Marino Gammazza, Michal Aleksander Zmijewski, Claudia Campanella, Francesco Cappello, Tomasz Wasiewicz, Alicja Kuban-Jankowska, Agnieszka Daca, Alicja Sielicka, Urszula Popowska, Narcyz Knap, Jakub Antoniewicz, Takashi Wakabayashi, Michal Wozniak

Affiliation

¹ Department of Medical Chemistry, Medical University of Gdansk, Gdansk, Poland.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylation
Antibiotics, Antineoplastic / pharmacology*
Apoptosis / drug effects*
Benzoquinones / pharmacology*
Bone Neoplasms / drug therapy*
Bone Neoplasms / metabolism
Cell Line, Tumor / drug effects
Cell Proliferation / drug effects
Cell Survival / drug effects
Chaperonin 60 / metabolism*
Drug Screening Assays, Antitumor
Humans
Lactams, Macrocyclic / pharmacology*
Mitochondria / metabolism
Mitochondrial Proteins / metabolism*
Osteosarcoma / drug therapy*
Osteosarcoma / metabolism
Protein Processing, Post-Translational
Protein Transport
Signal Transduction

Substances

Antibiotics, Antineoplastic
Benzoquinones
Chaperonin 60
HSPD1 protein, human
Lactams, Macrocyclic
Mitochondrial Proteins
geldanamycin

Grants and funding

This work was supported by grant of the Ministry of Science and Higher Education No. N N401 634140, and by Medical University of Gdansk Funding No. ST46. FC, AMG, and CC acknowledge support from Euro-Mediterranean Institute of Science and Technology, Palermo, Italy. MAZ acknowledges support from grant from Polish Ministry of Science and Higher Education, projects No. N405 623238 and N402 662840. MW and UP acknowledge support from College of Health, Beauty Care and Education in Poznan. AS acknowledges support from TEAM program of Foundation for Polish Science (TEAM/2011-8/7). NK acknowledges support from grant of the Ministry of Science and Higher Education No. N N401 572640. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.