The quinone methide aurin is a heat shock response inducer that causes proteotoxic stress and Noxa-dependent apoptosis in malignant melanoma cells [Signal Transduction]

December 4th, 2014 by Davis, A. L., Qiao, S., Lesson, J. L., Rojo de la Vega, M., Park, S. L., Seanez, C. M., Gokhale, V., Cabello, C. M., Wondrak, G. T.

Pharmacological induction of proteotoxic stress is rapidly emerging as a promising strategy for cancer cell-directed chemotherapeutic intervention. Here, we describe the identification of a novel drug-like heat shock response inducer for the therapeutic induction of proteotoxic stress targeting malignant human melanoma cells. Screening a focused library of compounds containing redox-directed electrophilic pharmacophores employing the Stress 4-[bis(p-hydroxyphenyl)methylene]-2,5-cyclohexadien-1-one] was identified as an experimental cell stress modulator that causes (i) heat shock factor transcriptional activation, (ii) upregulation of heat shock response gene expression (HSPA6, HSPA1A, DNAJB4, HMOX1), (iii) early unfolded protein response (UPR) signaling (phospho-PERK, phospho-eIF2α, CHOP), (iv) proteasome impairment with increased protein-ubiquitination, and (v) oxidative stress with glutathione depletion. Fluorescence polarization-based experiments revealed that aurin displays activity as a geldanamycin-competitive Hsp90α-antagonist, a finding further substantiated by molecular docking and ATPase inhibition analysis. Aurin exposure caused caspase-dependent cell death in a panel of human malignant melanoma cells (A375, G361, LOX-IMVI), but not in non-malignant human skin cells (Hs27 fibroblasts, HaCaT keratinocytes, primary melanocytes) undergoing the aurin-induced heat shock response without impairment of viability. Aurin-induced melanoma cell apoptosis depends on Noxa upregulation as confirmed by siRNA rescue experiments demonstrating that siPMAIP1-based target downregulation suppresses aurin-induced cell death. Taken together, our data suggest feasibility of apoptotic elimination of malignant melanoma cells using the quinone methide-derived heat shock response inducer aurin.
  • Posted in Journal of Biological Chemistry, Publications
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