Induction of HSP70 gene expression by the antiproliferative prostaglandin PGA₂: A growth-dependent response mediated by activation of heat shock transcription factor

Prostaglandins (PG) of the A series are potent inhibitors of cell proliferation. Recently, it was shown that PGA₂-induced growth arrest was associated with the increased synthesis of stress proteins encoded by the HSP70 gene family. In this study, we have examined the molecular basis for this increased HSP70 expression. Northern (RNA) blot analysis and nuclear run-on assays demonstrated that induction of high levels of HSP70 mRNA results from an increase in the rate of transcription. High-level induction is specific to the HSP70 family of heat shock proteins and is rapid, reversible, dose dependent, and specific for PGs capable of growth-arresting HeLa cells. In addition, the response was found to be highly dependent on the growth state of the cells, as induction occurs in growing but not in confluent nongrowing cell populations. Induction is dependent on the activation of heat shock factor. Cycloheximide pretreatment, which inhibits the antiproliferative effects of PGA₂, prevents activation of the heat shock factor and induction of HSP70 mRNA by PGA₂. These results support a role for HSP70 in mediating the antiproliferative effects of PGA₂.