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MUC1 Oncoprotein Blocks Death Receptor–Mediated Apoptosis by Inhibiting Recruitment of Caspase-8

Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts

Requests for reprints: Donald Kufe, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, MA 02115. Phone: 617-632-3141; Fax: 617-632-2934; E-mail: donald_kufe@dfci.harvard.edu.

Key Words: MUC1 • caspase-8 • death receptors • TNF • TRAIL • FasL • apoptosis

Stimulation of the death receptor superfamily induces the activation of caspase-8 and thereby the apoptotic response. The MUC1 oncoprotein is aberrantly overexpressed by diverse human malignancies and inhibits stress-induced apoptosis. The present results show that MUC1 blocks activation of caspase-8 and apoptosis in the response of malignant cells to tumor necrosis factor , tumor necrosis factor–related apoptosis-inducing ligand, and Fas ligand. The results show that MUC1 associates constitutively with caspase-8. The MUC1 cytoplasmic domain (MUC1-CD) binds directly to the caspase-8 p18 fragment upstream to the catalytic Cys³⁶⁰ site. The results also show that MUC1-CD binds to Fas-associated death domain (FADD) at the death effector domain. In nonmalignant epithelial cells, MUC1 interacts with caspase-8 and FADD as an induced response to death receptor stimulation. The functional significance of these interactions is supported by the demonstration that MUC1 competes with caspase-8 for binding to FADD and blocks recruitment of caspase-8 to the death-inducing signaling complex. These findings indicate that MUC1 is of importance to the physiologic regulation of caspase-8 activity and that overexpression of MUC1, as found in human malignancies, could contribute to constitutive inhibition of death receptor signaling pathways. [Cancer Res 2008;68(15):6136–44]

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