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N-Glycosylation of MDA-7/IL-24 Is Dispensable for Tumor Cell–Specific Apoptosis and "Bystander" Antitumor Activity

Departments of ¹ Urology, ² Pathology, and ³ Neurosurgery, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, College of Physicians and Surgeons, New York, New York; and ⁴ Department of Radiation Oncology and Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia

Requests for reprints: Paul B. Fisher, Departments of Pathology and Urology, Columbia University Medical Center, College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032. Phone: 212-305-3642; Fax: 212-305-8177; E-mail: pbf1{at}columbia.edu.

Biochemical and genetic mutation–based analyses confirm that the MDA-7/IL-24 protein can induce transformed cell–specific apoptosis through a mechanism involving endoplasmic reticulum (ER) stress–associated pathways. Covalent modifications by N-linked glycans in the ER contribute to the conformational maturation and biological functions of many proteins. Because MDA-7/IL-24 is a glycosylated protein, we investigated the role of glycosylation in mediating the specific biological and "bystander" antitumor activities of this cytokine. An adenovirus vector expressing a nonsecreted and nonglycosylated version of MDA-7/IL-24 protein was generated via deletion of its signal peptide and point mutations of its three N-glycosylated sites. In this study, we showed that this intracellular nonglycosylated protein was as effective as wild-type MDA-7/IL-24 protein in inducing apoptosis in multiple tumor cell lines. Both constructs (a) displayed transformed cell specificity and localization to the ER compartment, (b) mediated apoptosis through JAK/STAT-independent and p38^MAPK-dependent pathways, (c) induced sustained ER stress as evidenced by expression of ER stress markers (BiP/GRP78, GRP94, XBP-1, and eIF2), and (d) generated proteins that physically interacted with BiP/GRP78. Additionally, an expression construct containing the mda-7/IL-24 signal peptide linked to the mutated nonglycosylated mda-7/IL-24 gene retained the ability to induce bystander antitumor activity. These studies reveal that MDA-7/IL-24 glycosylation is not mandatory for inducing cell death or bystander activities in different cancer cells, providing new insights into the mechanism by which MDA-7/IL-24 induces apoptosis and ER stress. (Cancer Res 2006; 66(24): 11869-77)

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