Arsenic trioxide induces de novo protein synthesis of annexin-1 in neutrophils: association with a heat shock-like response and not apoptosis.

We recently demonstrated that arsenic trioxide (ATO) induced apoptosis in human neutrophils and increased de novo protein synthesis. Here, we identified one of these newly synthesized proteins as annexin-1 (AnxA1), a protein recently found to be proapoptotic in neutrophils when added exogenously. AnxA1 was detected at the cell membrane of ATO-induced neutrophils as well as in the supernatants. Using neutrophils harvested from AnxA1 knockout mice, we found that the proapoptotic activity of ATO was similar in neutrophils, regardless of AnxA1 levels. A second protein was identified as heat shock protein (Hsp) 89alpha. Because ATO is known to induce a HS-like response in a variety of cells, we investigated its ability to induce gene expression of Hsp in neutrophils and found that ATO increases HSP90AA1, HSPA1 and HSPB1 mRNA in these cells. We conclude that ATO-induced neutrophil apoptosis by an AnxA1-independent mechanism. Our data provide the first evidence that ATO induces a stress response in human neutrophils and that de novo synthesis of AnxA1 is related to this event rather than to the proapoptotic activity of ATO.