Celastrol, a natural substance isolated from
plant extracts used in
traditional Chinese medicine, has been extensively investigated as a possible
drug for treatment of
cancer,
autoimmune diseases, and
protein misfolding disorders. Although studies focusing on
celastrol's effects in specific cellular pathways have revealed a considerable number of targets in a diverse array of in vitro models there is an essential need for investigations that can provide a global view of its effects. To assess cellular effects of
celastrol and to identify target
proteins as
biomarkers for monitoring treatment regimes, we performed large-scale quantitative proteomics in cultured human lymphoblastoid cells, a cell type that can be readily prepared from human blood samples.
Celastrol substantially modified the
proteome composition and 158 of the close to 1800
proteins with robust quantitation showed at least a 1.5 fold change in
protein levels. Up-regulated
proteins play key roles in cytoprotection with a prominent group involved in quality control and processing of
proteins traversing the endoplasmic reticulum. Increased levels of
proteins essential for the cellular protection against oxidative stress including
heme oxygenase 1, several
peroxiredoxins and
thioredoxins as well as
proteins involved in the control of
iron homeostasis were also observed. Specific analysis of the mitochondrial
proteome strongly indicated that the mitochondrial association of certain
antioxidant defense and apoptosis-regulating
proteins increased in cells exposed to
celastrol. Analysis of selected
mRNA transcripts showed that
celastrol activated several different stress response pathways and dose response studies furthermore showed that continuous exposure to sub-micromolar concentrations of
celastrol is associated with reduced cellular viability and proliferation. The extensive catalog of regulated
proteins presented here identifies numerous cellular effects of
celastrol and constitutes a valuable
biomarker tool for the development and monitoration of disease treatment strategies.