Thiostrepton, a natural compound that triggers heat shock response and apoptosis in human cancer cells: a proteomics investigation.

Abstract

Thiostrepton is a natural antibiotic produced by bacteria of Streptomyces genus. We identified Thiostrepton as a strong hit in a cell-based small molecule screen for DIAP1 stability modulators. It was shown previously that Thiostrepton induces upregulation of several gene products in Streptomyces lividans, including the TipAS and TipAL isoforms, and that it can induce apoptotic cell death in human cancer cells. Furthermore, it was suggested that thiostrepton induces oxidative and proteotoxic stress, as inferred from the transcriptional upregulation of stress-related genes and endoplasmic reticulum (ER) stress genes. We used a combination of biochemical and proteomics approaches to investigate the effect of Thiostrepton and other compounds in human cells. Our mass-spectrometry data and subsequent biochemical validation shows that Thiostrepton (and MG-132 proteasome inhibitor) trigger upregulation of heat shock proteins HspA1A, Hsp70, Hsp90α, or Hsp105 in various human cancer cells. We propose a model where Thiostrepton-induced proteasome inhibition leads to accumulation of protein aggregates that trigger a heat shock response and apoptosis in human cancer cells.