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.
"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). "
"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 . 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 . 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 . "
[Show abstract][Hide abstract] ABSTRACT: The clinical efficacy of most therapeutic vaccines against cancer has not yet met its promise. Data are emerging that strongly support the notion that combining immunotherapy with conventional therapies, for example, radiation and chemotherapy may improve efficacy. In particular combination with chemotherapy may lead to improved clinical efficacy by clearing suppressor cells, reboot of the immune system, by rendering tumor cells more susceptible to immune mediated killing, or by activation of cells of the immune system. In addition, a range of tumor antigens have been characterized to allow targeting of proteins coupled to intrinsic properties of cancer cells. For example, proteins associated with drug resistance can be targeted, and form ideal target structures for use in combination with chemotherapy for killing of surviving drug resistant cancer cells. Proteins associated with the malignant phenotype can be targeted to specifically target cancer cells, but proteins targeted by immunotherapy may also simultaneously target cancer cells as well as suppressive cells in the tumor stroma.
BioMed Research International 06/2010; 2010(6):237623. DOI:10.1155/2010/237623 · 2.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In recent years, the combination of cancer immunotherapy with standard therapeutic modality is gaining credibility due to a number of clinical trials demonstrating therapeutic success of such combination therapies. However, the mechanism of this phenomenon is poorly understood. Here, we will discuss recent findings that suggest novel mechanisms of synergistic effect of cancer immunotherapy and chemotherapy.
Cancer Immunology and Immunotherapy 10/2010; 60(3):419-23. DOI:10.1007/s00262-010-0930-1 · 3.94 Impact Factor
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