title: Geldanamycin-induced osteosarcoma cell death is associated with hyperacetylation and loss of mitochondrial pool of heat shock protein 60 (hsp60).
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.
authors.affiliation: Department of Medical Chemistry, Medical University of Gdansk, Gdansk, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Gorska
authors.forename: Antonella
authors.initials: A
authors.lastname: Marino Gammazza
authors.forename: Michal Aleksander
authors.initials: MA
authors.lastname: Zmijewski
authors.forename: Claudia
authors.initials: C
authors.lastname: Campanella
authors.forename: Francesco
authors.initials: F
authors.lastname: Cappello
authors.forename: Tomasz
authors.initials: T
authors.lastname: Wasiewicz
authors.forename: Alicja
authors.initials: A
authors.lastname: Kuban-Jankowska
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Daca
authors.forename: Alicja
authors.initials: A
authors.lastname: Sielicka
authors.forename: Urszula
authors.initials: U
authors.lastname: Popowska
authors.forename: Narcyz
authors.initials: N
authors.lastname: Knap
authors.forename: Jakub
authors.initials: J
authors.lastname: Antoniewicz
authors.forename: Takashi
authors.initials: T
authors.lastname: Wakabayashi
authors.forename: Michal
authors.initials: M
authors.lastname: Wozniak
mesh_terms: D000107:Acetylation; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D016227:Benzoquinones / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018834:Chaperonin 60 / Q000378:metabolism*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism*; D012516:Osteosarcoma / Q000188:drug therapy* / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D015398:Signal Transduction
chemical_list: D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; D018834:Chaperonin 60; C060293:HSPD1 protein, human; D047029:Lactams, Macrocyclic; D024101:Mitochondrial Proteins; C001277:geldanamycin