1: Biochem Pharmacol. 2009 Feb 1;77(3):375-83. Epub 2008 Oct 28.

Hsp90 cleavage by an oxidative stress leads to its client proteins degradation
and cancer cell death.

Beck R, Verrax J, Gonze T, Zappone M, Pedrosa RC, Taper H, Feron O, Calderon PB.

Unité de Pharmacocinétique, Métabolisme, Nutrition, et Toxicologie, Département
des sciences pharmaceutiques, Université Catholique de Louvain, avenue E. Mounier
73, 1200 Brussels, Belgium.

The heat shock protein 90 (Hsp90) plays a crucial role in the stability of
several proteins that are essential for malignant transformation. Hsp90 is
therefore an interesting therapeutic target for cancer therapy. In this paper, we
investigated whether an oxidative stress generated during ascorbate-driven
menadione redox cycling (ascorbate/menadione), affects Hsp90 leading to the
degradation of some critical proteins and cell death. Unlike 17-AAG, which
inhibits Hsp90 but enhances Hsp70 levels, ascorbate/menadione-treated cells
present an additional Hsp90 protein band of about 70kDa as shown by Western blot 
analysis, suggesting Hsp90 cleavage. This Hsp90 cleavage seems to be a selective 
phenomenon since it was observed in a large panel of cancer cell lines but not in
non-transformed cells. Antibodies raised against either the N-terminus or the
C-terminus domains of Hsp90 suggest that the site of cleavage should be located
at its N-terminal part. Furthermore, antibodies raised against either the alpha- 
or the beta-Hsp90 isoform show that Hsp90beta is cleaved while the alpha isoform 
is down-regulated. We have further shown that different Hsp90 client proteins
like Bcr-Abl (a chimerical protein expressed in K562 leukemia cells), RIP and
Akt, were degraded when K562 cells were exposed to an oxidative stress. Both
Hsp90 cleavage and Bcr-Abl degradation were observed by incubating K562 cells
with another H(2)O(2)-generating system (glucose/glucose oxidase) and by
incubating KU812 cells (another leukemia cell line) with ascorbate/menadione. Due
to the major role of Hsp90 in stabilizing oncogenic and mutated proteins, these
results may have potential clinical applications.


PMID: 19014912 [PubMed - indexed for MEDLINE]

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