Ionizing radiation and chemotherapeutic drugs induce apoptosis in lymphocytes in the absence of Fas or FADD/MORT1 signaling. Implications for cancer therapy.
Ionizing radiation and cytotoxic drugs used in the treatment of cancer induce apoptosis in many cell types, including tumor cells. It has been reported that tumor cells treated with anticancer drugs increase surface expression of Fas ligand (FasL) and are killed by autocrine or paracrine apoptosis signaling through Fas (Friesen, C., I. Herr, P.H. Krammer, and K.-M. Debatin. 1996. Nat. Med. 2:574-577). We show that lymphocytes that cannot be killed by FasL, such as those from Fas-deficient lpr mice or transgenic mice expressing a dominant negative mutant of Fas-associated death domain protein (FADD/MORT1), are as sensitive as normal lymphocytes to killing by gamma radiation or the cytotoxic drugs cis-platin, doxorubicin, and etoposide. In contrast, p53 deficiency or constitutive expression of Bcl-2 markedly increased the resistance of lymphocytes to gamma radiation or anticancer drugs but had no effect on killing by FasL. Consistent with these observations, lpr and wild-type T cells both had a reduced capacity for mitogen-induced proliferation after drug treatment, whereas bcl-2 transgenic or p53-deficient T cells retained significant clonogenic potential. These results demonstrate that apoptosis induced by ionizing radiation or anticancer drugs requires p53 and is regulated by the Bcl-2 protein family but does not require signals transduced by Fas and FADD/MORT1.
Newton
K
K
Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3050, Australia.
Strasser
A
A
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D029681:Arabidopsis Proteins; D044943:Fatty Acid Desaturases / Q000502:physiology*; D008214:Lymphocytes / Q000187:drug effects / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000473:pathology / Q000628:therapy*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D019014:fas Receptor / Q000502:physiology*
D000970:Antineoplastic Agents; D029681:Arabidopsis Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D019014:fas Receptor; D044943:Fatty Acid Desaturases; C084083:Fad7 protein, Arabidopsis