Researchers at the Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, have published an interesting article investigating the relationship between protein homeostasis and the heat shock response.  The researchers maintain that some compounds – like withaferin A –  lead to thiol-reactive metabolites that compromise the ability of cancer cells to use Heat Shock Factor 1 (HSF1) to ensure survival.  The research is exciting in that all cancers make use of the HSF1-dependent stress response and therefore any such compounds found to be therapeutically effective would theoretically work against a broad range of cancers.

In the study, many such compounds were examined.  Interestingly, the natural compounds seemed to be the most active, specifically five classes thereof.  These five chemical classes all shared a functional motif: a thiol-reactive alpha, beta-unsaturated carbonyl group.  This group was found to be necessary to arrest tumour cell growth, yet not sufficient on its own.  Despite not elucidating a mechanistic model for this behaviour, the findings offer a glimpse into the functionality and importance of the HSF1 pathway and, more importantly, have discovered a new approach to finding candidate compounds that interrupt cancer activity – by disrupting protein homeostasis.

Specifically, HSF1 hyper-activation in cancer cells led to greater amounts of Hsp90 and Hsp27; allowing these cells to become more robust in the face of cellular shock and maintenance of protein homeostasis.  These HSP’s have been popular areas for development of therapeutic targets within the last decade.  This study looked to perturb the pathway further up the chain, namely, to interrupt the transcription of these proteins by deactivating HSF1, a novel method.  By establishing proper controls and a fluorescent cell line, the researchers screened 80,000 compounds, natural and synthetic, to isolate those inhibiting HSF1 activity.  By examining these “hits”, the common carbonyl motif was discovered.  Their importance was confirmed by removing this motif from the compounds, which led to impaired function.

The original research paper was published in: ACS Chemical Biology, online November 2011

Using the Heat-Shock Response to Discover Anticancer Compounds that Target Protein Homeostasis.

In this study, StressMarq monoclonal anti-Hsp72, product# SMC-100, was used in immunoblotting to determine changes in levels of the stress-induced Hsp70.