Inhibition of stress-inducible HSP70 impairs mitochondrial proteostasis and function

Julia I.Ju Leu, Thibaut Barnoud, Gao Zhang, Tian Tian, Zhi Wei, Meenhard Herlyn, Maureen E. Murphy, Donna L. George

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

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 nuclearencoded 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.

Original languageEnglish (US)
Pages (from-to)45656-45669
Number of pages14
JournalOncotarget
Volume8
Issue number28
DOIs
StatePublished - 2017

All Science Journal Classification (ASJC) codes

  • Oncology

Keywords

  • Chaperone
  • HSP70
  • Mitochondria
  • PABPC1
  • Proteostasis

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