Combined inhibition of Hsp90 and the proteasome affects NSCLC proteostasis and attenuates cell migration

Victoria Zismanov, Liat Drucker*, Maya Gottfried

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Lung cancer remains the most common cause of cancer-related death worldwide. This malignancy is a complex disease, and it is important to identify potential biological targets, the blockade of which would affect multiple downstream signaling cascades. A growing number of reports recognize novel therapeutic targets in the protein homeostasis network responsible for generating and protecting the protein fold. The heat shock protein 90 (Hsp90) is an essential molecular chaperon involved in the posttranslational folding and stability of proteins. It is required for conformational maturation of multiple oncogenic kinases that drive signal transduction and proliferation of cancer cells. However, in the case of unfolded protein accumulation endoplasmic reticulum (ER) stress is induced and several response pathways such as proteasome functions are activated. The ubiquitin-proteasome system orchestrates the turnover of innumerable cellular proteins. Here, we suggest that the therapeutic efficacy of Hsp90 inhibition may be augmented by coadministering proteasome inhibitor on human non-small-cell lung cancer (NSCLC) cell lines. Indeed, we showed that coadministration of the Hsp90 inhibitor 17-demethoxygeldanamycin (17-DMAG) and proteasome inhibitor (velcade) induced ER stress evidenced by increased unfolded protein response markers. The consequences were evident in multiple aspects of the NSCLC phenotype: reduced viability and cell count, increased apoptotic cell death, and most profoundly, synergistically decreased cell motility. Our findings provide proof-of-concept that targeting ER homeostasis is therapeutically beneficial in NSCLC cell lines.

Original languageEnglish
Pages (from-to)998-1006
Number of pages9
JournalAnti-Cancer Drugs
Volume25
Issue number9
DOIs
StatePublished - Oct 2014

Keywords

  • 17-DMAG
  • Endoplasmic reticulum homeostasis
  • Endoplasmic reticulum stress
  • Lung cancer
  • Unfolded protein response
  • Velcade

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