title: Differential impact of bortezomib on HL-60 and K562 cells.
abstract: Bortezomib (PS-341, or Velcade), reversible inhibitor of 20S proteasome approved for the treatment of multiple myeloma and mantle cell lymphoma, exhibited a cytotoxic effect toward other malignancies including leukaemia. In this study, we have documented that incubation of both HL-60 and K562 leukaemia cells with nanomolar concentrations of bortezomib is associated with the death of HL-60 cells observed within 24 hours of incubation with bortezomib and the death of K562 cells that were observed after 72 hours of incubation with bortezomib. The relative resistance of K562 cells to bortezomib correlated well with significantly higher expression of HSP27, HSP70, HSP90α, HSP90β and GRP75 in these cells. Incubation of both HL-60 and K562 cells with bortezomib induced a cleavage of HSP90β as well as expression of HSP70 and HSP90β but bortezomib did not affect levels of HSP27, HSP90α, GRP75 and GRP78. The death of both types of cells was accompanied with proteolytic activation of caspase 3 that was observed in HL-60 cells and proteolytic degradation of procaspase 3 in K562 cells. Our study has also pointed to essential role of caspase 8 in bortezomib-induced cleavage of HSP90β in both HL-60 and K562 cells. Finally, we have shown that bortezomib induced activation of caspase 9/caspase 3 axis in HL-60 cells, while the mechanism of death of K562 cells remains unknown.
authors.affiliation: Department of Medical Biochemistry, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin, Martin, Slovak Republic.
authors.forename: Katarína
authors.initials: K
authors.lastname: Kliková
authors.forename: Andrea
authors.initials: A
authors.lastname: Štefaniková
authors.forename: Ivana
authors.initials: I
authors.lastname: Pilchová
authors.forename: Jozef
authors.initials: J
authors.lastname: Hatok
authors.forename: Peter
authors.initials: P
authors.lastname: Chudý
authors.forename: Juraj
authors.initials: J
authors.lastname: Chudej
authors.forename: Dušan
authors.initials: D
authors.lastname: Dobrota
authors.forename: Peter
authors.initials: P
authors.lastname: Račay
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D016923:Cell Death; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D000091342:Endoplasmic Reticulum Chaperone BiP; D015973:Gene Expression Regulation, Leukemic; D018922:HL-60 Cells / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D020014:K562 Cells / Q000187:drug effects; D007938:Leukemia / Q000473:pathology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D000091342:Endoplasmic Reticulum Chaperone BiP; D018841:HSP90 Heat-Shock Proteins; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D011719:Pyrazines; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex