Selective depletion of inducible HSP70 enhances immunogenicity of rat colon cancer cells

Abstract

Expression of inducible heat shock protein 70 (HSP70) in tumor cells has been proposed to enhance their immunogenicity. However, HSP70 has also been demonstrated to prevent tumor cell death, a key process for the development of tumor cell immunogenicity. In the present study, we investigated the in¯uence of the HSP70 protein level on PRO colon cancer cell growth and immunogenicity in syngeneic BDIX rats and nude mice. These cells have a basal expression of HSP70 which can be substantially increased by heat shock. When injected subcutaneously in syngeneic animals, PRO cells do not induce any detectable immune response and give rise to progressive, metastatic and lethal tumors. Stable transfection of an anti-sense hsp70 cDNA in PRO cells (PRO-70AS cells) strongly decreased HSP70 expression and sensitized cell-free extracts to cytochrome c/dATPmediated activation of caspases. Subcutaneous injection of PRO-70AS cells induced tumors that rapidly regressed in syngeneic rats while they grew normally in nude mice. Syngeneic rats injected with PRO-70AS cells became protected against a further challenge with PRO cells. The tumor-speci®c immune response induced by HSP70-depleted PRO-70AS cells was associated with an increased rate of cell death in vivo. These PRO-70AS cells were also more sensitive to NO-mediated, caspasedependent, macrophage cytotoxicity in vivo. Altogether, these results indicate that reduced level of HSP70 expression in PRO-colon cancer cells results in the generation of a speci®c immune response by promoting cell death in vivo. Oncogene (2001) 20, 7478 ± 7485.

The Heat Shock Protein HSP70 Promotes Mouse NK Cell Activity against Tumors That Express Inducible NKG2D Ligands

“…Overexpression of HSP70 has been described in various tumors and has been found to be associated with enhanced tumorigenicity and resistance to therapy (2). In accordance with these findings, experimental down-regulation of HSP70 in tumor cells has been reported to enhance tumor regression in animal models (3)(4)(5).…”

Members of the heat-shock protein 70 family promote cancer cell growth by distinct mechanisms

“…Hsp70 is abundantly expressed in malignant tumors of various origins (for review, see Jäättelä 1999), and its expression correlates with increased cell proliferation, poor differentiation, lymph node metastases, and poor therapeutic outcome in human breast cancer (Ciocca et al 1993;Lazaris et al 1997;Vargas-Roig et al 1997. Furthermore, numerous experimental cancer models have demonstrated the tumorigenic potential of Hsp70 in rodents (Jäättelä 1995;Seo et al 1996;Volloch and Sherman 1999;Gurbuxani et al 2001). In support of the hypothesis that Hsp70 promotes tumorigenesis via its pro-survival function, it can effectively inhibit cell death induced by a wide range of stimuli including several cancer-related stresses like hypoxia, inflammatory cytokines, monocytes, irradiation, oxidative stress, and anticancer drugs (Jäättelä et al 1992(Jäättelä et al , 1998Jäättelä and Wissing 1993;Simon et al 1995;Mosser et al 1997;Buzzard et al 1998;Vayssier et al 1998;Nylandsted et al 2004).…”

Heat shock protein 70 binding inhibits the nuclear import of apoptosis-inducing factor

“…Clinical trials using a specific inhibitor of HSP90, 17-allylamino-17-demethoxygelda- namycin, are currently being performed with encouraging results (Munster et al, 2001). We and others have recently shown that downregulation of HSP70 with antisense constructs sensitizes to apoptosis induction and even can induce spontaneous cell death (Nylandsted et al, 2000;Gurbuxani et al, 2001). At least part of the cytoprotective action of HSP70 is mediated by its interaction with AIF, which does not depend on its chaperone activity.…”

“…HSP70 overexpression has been shown to increase the tumorigenicity of cancer cells in rodent models (Jaattela, 1995). Conversely, HSP70 downregulation is sufficient to kill tumour cells or to facilitate the induction of apoptosis (Nylandsted et al, 2000;Gurbuxani et al, 2001). The antiapoptotic function of HSP70 involves interactions with several components of the apoptotic machinery.…”