Abstract
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 FasL promoter-luciferase reporter gene to investigate effects of DNA topoisomerase (Topo) II inhibitors on FasL promoter activity. Transient transfection assays in HeLa and other tumor cell lines demonstrated that induction of FasL promoter activity in response to Topo II inhibitors such as VM-26 mimicked endogenous FasL expression under the same conditions. The ability of these agents to induce FasL 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 FasL 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 FasL induction, we found that DNA-damaging irradiation also induced FasL 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 FasL expression.
Footnotes
- Received June 18, 1998.
- Accepted November 10, 1998.
-
Send reprint requests to: Dr. William T. Beck, Division of Developmental Therapeutics, Cancer Center, University of Illinois at Chicago, Chicago, IL 60607-7173. E-mail: wtbeck{at}uic.edu
-
This work was supported in part by Research Grants CA40570 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services (Bethesda, MD), and ACS97–34 from the American Cancer Society, Illinois Division, Inc. (Chicago, IL), and in part by the Cancer Center, University of Illinois at Chicago.
- The American Society for Pharmacology and Experimental Therapeutics
MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|