Human HspB1 (Hsp27), a molecular chaperone bearing tumorigenic and metastatic roles, is
characterized by its dynamic phosphorylation and heterogenous oligomerization in response to changes in cell
physiology. The phenomenon is particularly intense and specific when cells are exposed to different death
inducers. This favors the hypothesis that the structural organization of HspB1 acts as a sensor which, through
reversible modifications, allows cells to adapt and/or mount a protective response. A large number of HspB1
interacting partners have already been described in the literature. Specific changes in oligomerphosphorylation
organization may therefore allow HspB1 to interact with the more appropriate polypeptides
and to subsequently modulate their folding/activity and/or half-life. This could indirectly link HspB1 to multiple
cellular functions and could explain the apparently unrelated effects associated to its over- or underexpression.
In cancer, HspB1 is tumorigenic, stimulates metastasis and provide cancer cells with resistance to
many anti-cancer drugs, so compounds aimed at disrupting HspB1 deleterious pro-cancer activity are actively
looked for. One example, is brivudine that impairs HspB1 ability to recognize pathological protein substrates
and appears as a promising anti-cancer drug. Similarly, we have observed that peptide aptamers that
specifically interfere with HspB1 structural organization reduced its anti-apoptotic and tumorigenic activities.
We propose that, in addition to RNA interference approaches, the tumorigenic activity of HspB1 could be
inhibited by altering HspB1 structural organization and consequently its interaction with inappropriate procancerous
polypeptide partners. Hence, developping HspB1 structure-based interfering strategies could lead
to new anti-cancer drugs discovery.
Keywords: Anti-cancer drugs, apoptosis, aptamers, cancer, Hsp27, HspB1, oligomerization, phosphorylation, heat shock proteins, protein folding, chaperone, polypeptides, aggregation, proteasome proteolytic pathway, Alexander disease
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Published on: 03 October, 2012
Page: [1151 - 1163]