HspB1 Dynamic Phospho-Oligomeric Structure Dependent Interactome as Cancer Therapeutic Target

Author(s): A.-P. Arrigo, B. Gibert.

Journal Name: Current Molecular Medicine

Volume 12 , Issue 9 , 2012

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Abstract:

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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Article Details

VOLUME: 12
ISSUE: 9
Year: 2012
Page: [1151 - 1163]
Pages: 13
DOI: 10.2174/156652412803306693
Price: $58

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