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Inhibition of stress-inducible HSP70 impairs mitochondrial proteostasis and function.
- Source :
-
Oncotarget [Oncotarget] 2017 Jul 11; Vol. 8 (28), pp. 45656-45669. - Publication Year :
- 2017
-
Abstract
- Protein quality control is an important component of survival for all cells. The use of proteasome inhibitors for cancer therapy derives from the fact that tumor cells generally exhibit greater levels of proteotoxic stress than do normal cells, and thus cancer cells tend to be more sensitive to proteasome inhibition. However, this approach has been limited in some cases by toxicity to normal cells. Recently, the concept of inhibiting proteostasis in organelles for cancer therapy has been advanced, in part because it is predicted to have reduced toxicity for normal cells. Here we demonstrate that a fraction of the major stress-induced chaperone HSP70 (also called HSPA1A or HSP72, but hereafter HSP70) is abundantly present in mitochondria of tumor cells, but is expressed at quite low or undetectable levels in mitochondria of most normal tissues and non-tumor cell lines. We show that treatment of tumor cells with HSP70 inhibitors causes a marked change in mitochondrial protein quality control, loss of mitochondrial membrane potential, reduced oxygen consumption rate, and loss of ATP production. We identify several nuclear-encoded mitochondrial proteins, including polyadenylate binding protein-1 (PABPC1), which exhibit decreased abundance in mitochondria following treatment with HSP70 inhibitors. We also show that targeting HSP70 function leads to reduced levels of several mitochondrial-encoded RNA species that encode components of the electron transport chain. Our data indicate that small molecule inhibitors of HSP70 represent a new class of organelle proteostasis inhibitors that impair mitochondrial function in cancer cells, and therefore constitute novel therapeutics.
- Subjects :
- Adenosine Triphosphate metabolism
Cell Line, Tumor
HSP70 Heat-Shock Proteins antagonists & inhibitors
Humans
Membrane Potential, Mitochondrial drug effects
Mitochondrial Proteins metabolism
Neoplasms drug therapy
Neoplasms genetics
Neoplasms metabolism
Neoplasms mortality
Poly(A)-Binding Protein I metabolism
Prognosis
Protein Binding
HSP70 Heat-Shock Proteins metabolism
Mitochondria drug effects
Mitochondria metabolism
Proteasome Inhibitors pharmacology
Proteostasis drug effects
Stress, Physiological
Subjects
Details
- Language :
- English
- ISSN :
- 1949-2553
- Volume :
- 8
- Issue :
- 28
- Database :
- MEDLINE
- Journal :
- Oncotarget
- Publication Type :
- Academic Journal
- Accession number :
- 28484090
- Full Text :
- https://doi.org/10.18632/oncotarget.17321