Cell-surface expression of Hsp70 on hematopoietic cancer cells after inhibition of HDAC activity

Laboratory of Immunology, Faculty of Life Sciences, University of Copenhagen, 1870 Frederiksberg C, Denmark.
Journal of leukocyte biology (Impact Factor: 4.29). 07/2009; 86(4):923-32. DOI: 10.1189/jlb.0209056
Source: PubMed


We show that inhibition of HDAC activity leads to surface expression of Hsp70 on various hematopoietic cancer cells, an occurance that was not observed on naïve or activated peripheral blood cells. HDAC inhibitor-mediated Hsp70 surface expression was confined to the apoptotic Annexin V-positive cells and blocked by inhibition of apoptosis. Other chemotherapeutic inducers of apoptosis such as etoposide and camptothecin also led to a robust induction of Hsp70 surface expression. Hsp70 expression was, however, not caused by induction of apoptosis per se, as activated CD4 T cells remained Hsp70 surface-negative despite effective induction of apoptosis. Interestingly, inhibition of endolysosomes or normal ER/Golgi transport did not affect Hsp70 surface expression. Intracellular calcium and the transcription factor Sp1, which has been shown previously to be important for the intracellular stress mediated by HDAC inhibitors, were not involved in Hsp70 surface expression. We also found that HDAC inhibitors decreased cellular PMET activity and that a selective inhibition of PMET activity with extracellular NADH induced a robust Hsp70 surface expression. Our data suggest that inhibition of HDAC activity selectively induces surface expression of Hsp70 on hematopoietic cancer cells and that this may increase immunorecognition of these cells.

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    • "Like HSP90, HSP70 can bind to the dephosphorylated turn motif of PKC and stabilise its conformation, and, in turn, promote its rephosphorylation and catalytic competence (Gao & Newton, 2002) (Figure 3E). This may be important because HSP70 is upregulated in cells undergoing stress, such as in response to chemotherapeutic agents (Jensen, et al., 2009). "

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    • "In this respect, HMGB-1 localization in the cytosol is associated with autophagy and cellular escape from apoptosis, in turn conferring resistance to several therapies including immunotherapy [74]. Also heat shock proteins (HSPs) which are upregulated upon specific stress may act as danger signals and be expressed on the cell surface as “eat me” signals to DC [76]. Interestingly, it has been shown that treatment of myeloma cells with the proteasome inhibitor bortezomib leads to surface expression of HSP90 on the cell surface [77]. "
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