Abstract
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 co-chaperone complex or mitochondrial Hsp90 homolog, TRAP1 involved hydrogen bonds, π-π stacking, cation-π 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.
Highlights
Despite the pervasive glycolytic metabolism of most tumors, the so-called “Warburg effect” [1], there is resurgent interest in the role of mitochondria in cancer [2, 3]
We have shown that subcellular targeting of small molecule Heat Shock Protein-90 (Hsp90) antagonists to mitochondria is feasible, “portable” across diverse chemical scaffolds, and confers much improved anticancer activity compared to the corresponding, nontargeted compounds
In terms of molecular recognition, mitochondrial targeting of PU-H71 resulted in greater selectivity for mitochondrial vs. cytosolic Hsp90, concurrently with a 10-fold lower binding energy with the mitochondrial Hsp90 homolog, TNFR-Associated Protein-1 (TRAP1)
Summary
Despite the pervasive glycolytic metabolism of most tumors, the so-called “Warburg effect” [1], there is resurgent interest in the role of mitochondria in cancer [2, 3] This is because mitochondrial bioenergetics is preserved in most malignancies [4], ATP produced via oxidative phosphorylation supports tumor growth, in vivo [5], and reprogramming of mitochondrial functions promotes key cancer traits, including drug resistance [6], “stemness” [7], and disease dissemination to distant organs, or metastasis [8, 9]. These molecules prominently accumulate in mitochondria of most tumors, compared to normal cells [14], where they buffer proteotoxic stress [15, 16], maintain a multifunctional mitochondrial “proteome” [17], and sustain primary and metastatic tumor growth, in vivo [18, 19]
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