DNA damage signals induction of Fas ligand in tumor cells

Many anticancer agents exert their cytotoxicity through DNA damage and indu ction of apoptosis. Fas ligand (FasL), a key component of T lymphocytes, ha s been shown to be induced by some of those agents. To address what is an e arly signal for this induction, we constructed a Fast promoter-luciferase r eporter gene to investigate effects of DNA topoisomerase (Topo) II inhibito rs on Fast promoter activity. Transient transfection assays in HeLa and oth er tumor cell lines demonstrated that induction of Fast promoter activity i n response to Topo II inhibitors such as VM-26 mimicked endogenous Fast exp ression under the same conditions. The ability of these agents to induce Fa st expression correlated with their ability to cause DNA damage. For instan ce, complex-stabilizing Topo II inhibitors such as etoposide, teniposide, a nd doxorubicin, which cause DNA damage, strongly induce Fast expression; by contrast, non-DNA-damaging catalytic Topo II inhibitors such as ICRF-187 a nd merbarone do not do this. In support of the notion that DNA damage trigg ers Fast induction, we found that DNA-damaging irradiation also induced Fas t promoter activity in a dose-dependent manner. Finally, the catalytic Topo II inhibitor ICRF-187 suppressed VM-26-induced-FasL expression. This suppr ession correlated with the ability of this drug to inhibit VM-26-induced DN A strand breaks. Together, our results suggest that DNA damage in response to agents such as etoposide and teniposide might serve as an early signal t o induce Fast expression.