DNA damage signals induction of Fas ligand in tumor cells

Many anticancer agents exert their cytotoxicity through DNA damage and induction of apoptosis. Fas ligand (FasL), a key component of T lymphocytes, has been shown to be induced by some of those agents. To address what is an early signal for this induction, we constructed a Fast promoter-luciferase reporter gene to investigate effects of DNA topoisomerase (Topo) II inhibitors on Fast promoter activity. Transient transfection assays in HeLa and other tumor cell lines demonstrated that induction of Fast promoter activity in response to Topo II inhibitors such as VM-26 mimicked endogenous Fast expression under the same conditions. The ability of these agents to induce Fast expression correlated with their ability to cause DNA damage. For instance, complex-stabilizing Topo II inhibitors such as etoposide, teniposide, and doxorubicin, which cause DNA damage, strongly induce Fast expression; by contrast, non-DNA-damaging catalytic Topo II inhibitors such as ICRF-187 and merbarone do not do this. In support of the notion that DNA damage triggers Fast induction, we found that DNA-damaging irradiation also induced Fast promoter activity in a dose-dependent manner. Finally, the catalytic Topo II inhibitor ICRF-187 suppressed VM-26-induced-FasL expression. This suppression correlated with the ability of this drug to inhibit VM-26-induced DNA strand breaks. Together, our results suggest that DNA damage in response to agents such as etoposide and teniposide might serve as an early signal to induce Fast expression.