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

Abstract

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.

Antileukemic activity of the HSP70 inhibitor pifithrin-μ in acute leukemia

“…22, 24, 29 This is mainly attributed to a compensatory upregulation of HSP70 as a result of HSP90 inhibition. In accordance with previous studies, 42, 43 we could demonstrate that both 17-AAG and SAHA treatment led to increased HSP70 levels in NALM-6 cells. Thus, functional abrogation of the HSP70 response induced by HSP90 and histone deacetylase inhibitors may explain the remarkable antiproliferative effects of PFT-μ in combination with SAHA and especially with 17-AAG.…”

Targeting Hsp70: A possible therapy for cancer

“…Inhibitors of Hsp70 and Hsp90 combined with histone deacetylase inhibitors increase the cell surface expression of Hsp70 on hematopoietic cancer cells [159]. An early response of extracellular Hsp70 is to activate suppressive myeloid immune cells [160].…”

Regulation of NKG2D-ligand cell surface expression by intracellular calcium after HDAC-inhibitor treatment

“…Appropriate IgG isotype controls were purchased from BD Biosciences. Annexin V and PI staining was done as previously described (Jensen et al, 2009). Flow cytometry analysis and data acquisition was performed on an Accuri C6 Flow Cytometer.…”