Nuria Vilaboa
Hospital Universitario La Paz-IdiPAZ, 28046 Madrid, Spain
Richard Voellmy
HSF Pharmaceuticals SA, 1814 La Tour-de-Peilz, Switzerland
Keywords:
proteostasis, protein unfolding, protein aggregation, Withaferin A, celastrol, IHSF
Abstract
Withaferin A (WA) and celastrol (CEL) are major bioactive components of plants that have been widely employed in traditional medicine. The pleiotropic activities of plant preparations and the isolated compounds in vitro and in vivo have been documented in hundreds of studies. Both WA and CEL were shown to have anticancer activity. Although WA and CEL belong to different chemical classes, our synthesis of the available information suggests that the compounds share basic mechanisms of action. Both WA and CEL bind covalently to numerous proteins, causing the partial unfolding of some of these proteins and of many bystander proteins. The resulting proteotoxic stress, when excessive, leads to cell death. Both WA and CEL trigger the activation of the unfolded protein response (UPR) which, if the proteotoxic stress persists, results in apoptosis mediated by the PERK/eIF-2/ATF4/CHOP pathway or another UPR-dependent pathway. Other mechanisms of cell death may play contributory or even dominant roles depending on cell type. As shown in a proteomic study with WA, the compounds appear to function largely as electrophilic reactants, indiscriminately modifying reachable nucleophilic amino acid side chains of proteins. However, a remarkable degree of target specificity is imparted by the cellular context.
Keywords: proteostasis, protein unfolding, protein aggregation, Withaferin A, celastrol, IHSF
Author Biography
Nuria Vilaboa, Hospital Universitario La Paz-IdiPAZ, 28046 Madrid, Spain
CIBER de Bioingenieria, Biomateriales y Nanomedicina, CIBER-BBN, 28046 Madrid, Spain
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