期刊
ONCOTARGET
卷 8, 期 68, 页码 112184-112198出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.23097
关键词
mitochondria; chaperone; Hsp90; acute myeloid leukemia; metabolism
资金
- National Institutes of Health (NIH) [P01 CA140043, R01 CA78810, CA190027]
- Office of the Assistant Secretary of Defense for Health Affairs through the Prostate Cancer Research Program [W81XWH-13-1-0193, UH2TR001373, CA205607, CA167708]
- Challenge Award from the Prostate Cancer Foundation (PCF)
- Cancer Center Support Grant (CCSG) [CA010815]
Reprogramming of mitochondrial functions sustains tumor growth and may provide therapeutic opportunities. Here, we targeted the protein folding environment in mitochondria by coupling a purine-based inhibitor of the molecular chaperone Heat Shock Protein-90 (Hsp90), PU-H71 to the mitochondrial-targeting moiety, triphenylphosphonium (TPP). Binding of PU-H71-TPP to ADP-Hsp90, Hsp90 cochaperone complex or mitochondrial Hsp90 homolog, TRAP1 involved hydrogen bonds, p-p stacking, cation-p contacts and hydrophobic interactions with the surrounding amino acids in the active site. PU-H71-TPP selectively accumulated in mitochondria of tumor cells (17-fold increase in mitochondria/cytosol ratio), whereas unmodified PU-H71 showed minimal mitochondrial localization. Treatment of tumor cells with PU-H71-TPP dissipated mitochondrial membrane potential, inhibited oxidative phosphorylation in sensitive cell types, and reduced ATP production, resulting in apoptosis and tumor cell killing. Unmodified PU-H71 had no effect. Bioinformatics analysis identified a mitochondrial Hsp90 signature in Acute Myeloid Leukemia (AML), which correlates with worse disease outcome. Accordingly, inhibition of mitochondrial Hsp90s killed primary and cultured AML cells, with minimal effects on normal peripheral blood mononuclear cells. These data demonstrate that directing Hsp90 inhibitors with different chemical scaffolds to mitochondria is feasible and confers improved anticancer activity. A potential addiction to mitochondrial Hsp90s may provide a new therapeutic target in AML.
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