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] Related Links Oxidative stress by ascorbate/menadione association kills K562 human chronic myelogenous leukaemia cells and inhibits its tumour growth in nude mice. [Biochem Pharmacol. 2006] PMID:16828058 Role of glycolysis inhibition and poly(ADP-ribose) polymerase activation in necrotic-like cell death caused by ascorbate/menadione-induced oxidative stress in K562 human chronic myelogenous leukemic cells. [Int J Cancer. 2007] PMID:17163414 Inhibition of heat shock protein 90 function by 17-allylamino-17-demethoxy-geldanamycin in Hodgkin's lymphoma cells down-regulates Akt kinase, dephosphorylates extracellular signal-regulated kinase, and induces cell cycle arrest and cell death. [Clin Cancer Res. 2006] PMID:16428504 [The mechanism of apoptosis of chronic myeloid leukemia cells induced by the novel p210 bcr/abl inhibitor berbamine] [Zhonghua Yi Xue Za Zhi. 2006] PMID:17064567 Novel oxime derivatives of radicicol induce erythroid differentiation associated with preferential G(1) phase accumulation against chronic myelogenous leukemia cells through destabilization of Bcr-Abl with Hsp90 complex. [Blood. 2000] PMID:10979978