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Stat1-dependent Induction of Tumor Necrosis Factor-related Apoptosis-inducing Ligand and the Cell-Surface Death Signaling Pathway by Interferon ß in Human Cancer Cells¹

Department of Surgery, Division of Surgical Oncology [E. A. C., D. J. M., H. L., D. L. F., F. R. S.], Institute of Human Gene Therapy [W. S. e-D., J. M. W., F. R. S.], Laboratory of Molecular Oncology and Cell Cycle Regulation, Howard Hughes Medical Institute, Departments of Medicine, Pharmacology, Genetics, Cancer Center [W. S. E.], University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104, and Biogen, Inc., Cambridge, Massachusetts 02142 [J. B.]

Type I IFNs are known to inhibit tumor cell growth and stimulate the immune system. However, little is known of the mechanism of type I IFN-induced apoptosis in human cancer cells. In this study, we have IFN-ß treatment of a human colorectal cell line (KM12L4) and a resistant clone of this cell line, L4RIFN. We demonstrate the induction of apoptosis in the parent cell line. This process was associated with the induction of the Jak-Stat signaling pathway, induction of the proapoptotic mediator tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), and activation of procaspase-3, -8, -9, and -10. Additionally, we evaluated the role of Stat1 in mediating IFN-ß induction of these proapoptotic signals in a fibrosarcoma cell line (2ftgh) and a Stat1-deficient clone (U3A). Our results demonstrate that IFN-ß induction of apoptosis and the induction of proapoptotic mediator TRAIL is Stat1 dependent. Evaluation of a stable transfectant of the KM12L4 cell line expressing c-FLIP supports the role of TRAIL and the cell-surface death signaling pathways in IFN-ß induction of apoptosis. Studies evaluating the TRAIL promoter indicate induction of TRAIL promoter activity by IFN-ß. These results may represent a novel pathway by which IFN-ß may induce therapeutic effects.

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