Forskning ved Københavns Universitet - Københavns Universitet

Forside

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

Publikation: KonferencebidragPosterForskning

  • Helle Jensen

The function of Hsp70 depends on its cellular location: When located intracellularly it exerts cytoprotective and anti-apoptotic functions, whereas it exerts immunostimulatory functions when located extracellularly. Secreted Hsp70 is for example involved in cross-presentation of cancer-derived antigenic peptides, a function which is currently explored in immunotherapeutic approaches against cancer. Additionally, membrane-bound Hsp70 can stimulate antigen presenting cells to release proinflammatory cytokines and can provide a target structure for NK cell-mediated lysis.

Human cancer cells frequently express Hsp70 on their cell surface, whereas the corresponding normal tissues do not. In addition, several clinically applied reagents, such as alkyl-lysophospholipides, chemotherapeutic agents, and anti-inflammatory reagents, have been found to enhance Hsp70 cell surface expression on cancer cells.

We have found that inhibition of histone deacetylase (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 cell 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 cell surface expression was however not caused by induction of apoptosis per se, since cells overexpressing Hsp70 did not become Hsp70 positive after Fas-induced apoptosis. Interestingly, inhibition of endolysosomal function or normal ER/Golgi transport did not affect Hsp70 cell surface expression. Moreover no secretion of soluble Hsp70 was observed. Thus the mechanism of transport and cell surface binding of Hsp70 after HDAC-inhibitor treatment remains elusive.

Our data suggest that inhibition of HDAC activity selectively induces cell surface expression of Hsp70 on hematopoietic cancer cells, and this may increase the immunorecognition of these cells. It could be envisaged that dying tumor cells expressing Hsp70 will attract and activate NK cells and macrophages, pushing the balance toward immunity against the tumor. Thus surface expressed Hsp70 may have functions reaching beyond the cell expressing it.

OriginalsprogEngelsk
Publikationsdato2010
StatusUdgivet - 2010
BegivenhedKeystone Symposia - Role of inflammation in oncogenesis - Keystone, USA
Varighed: 7 feb. 201012 feb. 2010

Konference

KonferenceKeystone Symposia - Role of inflammation in oncogenesis
LandUSA
ByKeystone
Periode07/02/201012/02/2010

ID: 17653916