Abstract
The major stress-inducible protein Hsp70 (HSPA1A) is overexpressed in the cytosol of many highly aggressive tumor cells including glioblastoma multiforme and presented on their plasma membrane. Depending on its intracellular or membrane localization, Hsp70 either promotes tumor growth or serves as a target for natural killer (NK) cells. The kinetics of the membrane Hsp70 (mHsp70) density on human glioma cells (U87) was studied after different irradiation doses to define the optimal therapeutic window for Hsp70-targeting NK cells. To maintain the cells in the exponential growth phase during a cultivation period of 7 days, different initial cell counts were seeded. Although cytosolic Hsp70 levels remained unchanged on days 4 and 7 after a sublethal irradiation with 2, 4 and 6 Gy, a dose of 2 Gy resulted in an upregulated mHsp70 density in U87 cells which peaked on day 4 and started to decline on day 7. Higher radiation doses (4 Gy, 6 Gy) resulted in an earlier and more rapid onset of the mHsp70 expression on days 2 and 1, respectively, followed by a decline on day 5. Membrane Hsp70 levels were higher on cells in G2/M than in G1; however, an irradiation-induced cell cycle arrest on days 4 and 7 was not associated with an increase in the mHsp70 density. Extracellular Hsp70 concentrations in the supernatant of irradiated cells were significantly higher than sham (0 Gy) irradiated cells on days 4 and 7, but not on day 1. Functionally, elevated mHsp70 densities were associated with a significantly better lysis by Hsp70-targeting NK cells. In summary, the kinetics of changes in the mHsp70 density upon irradiation on tumor cells is time- and dose-dependent.
Highlights
The therapeutic application of ionizing radiation, either alone or in combination with surgery and chemotherapy, plays a pivotal role in the treatment of solid tumors
While cytosolic heat shock protein 70 (Hsp70) is mainly responsible for maintaining protein homeostasis and protection against programmed cell death [3,5], membrane Hsp70 (mHsp70) mediates dual functions: on the one hand it stabilizes lysosomal and plasma membranes and thereby can prevent apoptosis [20,21], on the other hand, it provides a tumor-specific target for natural killer (NK) cells that have been pre-activated with Hsp70 plus low-dose IL-2 [8,15]
By its exclusive expression on the surface of tumor cells, but not normal cells [9], mHsp70 serves as a tumor-specific target for activated NK cells [10]
Summary
The therapeutic application of ionizing radiation, either alone or in combination with surgery and chemotherapy, plays a pivotal role in the treatment of solid tumors. The major goal of irradiation is to achieve local tumor control and a decreased dissemination by reducing the viable tumor mass, immunostimulatory effects have been assigned to ionizing radiation [1,2]. It remains to be elucidated which dose and radiation regimen is optimal to induce anti-tumor immune effects. By stimulating the overexpression of anti-apoptotic proteins (Bcl-2/Bcl-xL), downregulating pro-apoptotic Bax, Bcl-Xs and Bak or blocking tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-induced apoptosis and formation of the death-inducing signaling complex with death receptors DR4 and DR5 [5], cytosolic Hsp promotes tumor cell survival, protects against apoptosis and promotes tumor progression [6]
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