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• W2076758971 abstract "Cancer results from genetic and epigenetic alterations that deregulate cell growth, checkpoints and threshold for cell death. The growing cancer mass exhibits metabolic and protein-misfolding/denaturing stress due to hypoxia, deprivation of nutrients, acidosis and increased reactive oxygen species (ROS). Ubiquitin/proteasome system clears the mass of misfolded proteins, which are continuously generated through mutations and various denaturing stresses in cancer cells. Heat shock proteins (hsp) 90 and hsp70 induced by heat shock factor-1 (HSF-1) are at the center of an ATP-dependent chaperone network that promotes protein refolding, prevents protein aggregation, as well as targets misfolded proteins for destruction through the proteasome. Indeed, inhibition of hsp90 and hsp70 not only promotes degradation of hsp90 client oncoproteins, e.g., HER-2, c-RAF, AKT, FLT-3, BCR-ABL, androgen and estrogen receptors and HIF-1, but also induces the unfolded protein response (UPR) and endoplasmic reticulum (ER) stress. Importantly, following exposure to chemical carcinogens and the stress of oncogene mutations, mice lacking HSF-1 exhibit a much lower incidence of tumors and the tumor burden. In cancer cells, the metabolic stress and higher levels of misfolded and ubiquitylated proteins also promote autophagy. The predominantly cytosolic, class II histone deacetylase 6 (HDAC6) has been recently recognized as the cellular stress surveillance factor. This activity of HDAC6 resides in its ability to bind and deacetylate hsp90 and hsp70, as well as on its high affinity for binding misfolded and polyubiquitylated proteins through its C-terminal BUZ domain. Following its association with the misfolded and polyubiquitylated proteins through its BUZ domain, HDAC6 dissociates from the complex that also includes hsp90 and HSF-1, releasing HSF-1 from hsp90 to translocate to nucleus and induce heat shock proteins. HDAC6 also shuttles the misfolded and polyubiquitylated proteins into the protective cellular organelle, the perinuclear aggresome, where these proteins are degraded and recycled. To carry out all of these functions, the catalytic activity of HDAC6 is necessary. Treatment of transformed cells with the pan-HDAC inhibitors, which also inhibit HDAC6, induces hyeracetylation and abrogation of chaperone function of hsp90 and hsp70, inhibits the aggresome formation, as well as induces ROS and apoptosis. Hyperacetylation of hsp70 has also been recently found to promote the initiation of the phagaphore formation through stabilization of the complex between Vps34, Beclin-1 and hsp70. These novel insights into the roles of HDAC6 and hsp90/hsp/70 chaperone network in the non-oncogenic stress phenotype have also highlighted potential combinations as novel therapies. These include combined therapy with pan-HDAC or hsp90 inhibitors and/or proteasome or autophagy inhibitors. Overall, how these novel therapies should be integrated with other targeted agents in the treatment of advanced cancer. Citation Information: Clin Cancer Res 2010;16(7 Suppl):PL5-1" @default.
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• W2076758971 date "2010-04-01" @default.
• W2076758971 modified "2023-09-27" @default.
• W2076758971 title "Abstract PL5-1: Targeting the nexus of heat shock and metabolic stress responses in cancer" @default.
• W2076758971 doi "https://doi.org/10.1158/1078-0432.tcme10-pl5-1" @default.
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