Heat shock proteins: endogenous modulators of apoptotic cell death.

The highly conserved heat shock proteins (Hsps) accumulate in cells exposed to heat and a variety of other stressful stimuli. Hsps, that function mainly as molecular chaperones, allow cells to adapt to gradual changes in their environment and to survive in otherwise lethal conditions. The events of cell stress and cell death are linked and Hsps induced in response to stress appear to function at key regulatory points in the control of apoptosis. Hsps include anti-apoptotic and pro-apoptotic proteins that interact with a variety of cellular proteins involved in apoptosis. Their expression level can determine the fate of the cell in response to a death stimulus, and apoptosis-inhibitory Hsps, in particular Hsp27 and Hsp70, may participate in carcinogenesis. This review summarizes the apoptosis-regulatory function of Hsps.

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

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 influence 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/dATP-mediated 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-specific 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, caspase-dependent, 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 specific immune response by promoting cell death in vivo.