Tamoxifen induces apoptosis in Fas+ tumor cells by upregulating the expression of Fas ligand.
OBJECTIVE
Tamoxifen (TAM), a nonsteroidal anticancer agent, is used in the treatment of breast cancer. In the current study, we investigated whether TAM induces apoptosis in tumor cells by altering the expression of Fas and Fas ligand (FasL).


METHODS
Several tumor cell lines were used to test the ability of TAM to induce apoptosis, which was studied using the TUNEL assay. The effect of TAM on the expression of Fas and FasL was analyzed using a flow cytometer.


RESULTS
TAM was found to suppress the growth of an estrogen receptor-positive human mammary tumor cell line (T-47D) by inducing apoptosis. Interestingly, TAM also induced apoptosis in an estrogen receptor-negative murine T cell lymphoma cell line, EL-4. The ability of TAM to induce apoptosis in T-47D and EL-4 tumor cells correlated with the increased expression of FasL but not Fas on the tumor cells. Similar to TAM, a metalloproteinase (MP) inhibitor, which is known to increase the expression of membrane-bound FasL, was found to induce apoptosis in both T-47D and EL-4 tumor cells by increasing the expression of FasL but not Fas. Furthermore, both TAM and the MP inhibitor failed to induce apoptosis in L1210 tumor cell lines that failed to express FasL.


CONCLUSIONS
The current study demonstrates that TAM can induce apoptosis in Fas(+) tumor cells by upregulating FasL.
Molecular Nutrition Laboratory, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA.
Nisha
N
Nagarkatti
Barbara A
BA
Davis
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D004151:Dipeptides / Q000494:pharmacology; D053222:Fas Ligand Protein; D006801:Humans; D007939:Leukemia L1210 / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008223:Lymphoma / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D009369:Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D013629:Tamoxifen / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D019014:fas Receptor / Q000096:biosynthesis*
D016588:Anticarcinogenic Agents; D004151:Dipeptides; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505662:Faslg protein, rat; D008562:Membrane Glycoproteins; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D019014:fas Receptor; D013629:Tamoxifen; D008666:Metalloendopeptidases