Breast Cancer Cell Selective Apoptosis Induced by the Novel Activity of an IL-10 Related Cytokine

摘要

Preliminary data document that signaling events loading to Ad.mda-7- induced transformed-cell specific apoptosis are tyrosine kinase-independent. These results suggest that mda-7/IL-24 cancer cell-specific activity could occur through mechanisms independent of binding to its currently recognized cognate receptors and might even occur independent of receptor function. An adenovirus vector expressing a non-secreted version of MDA-7/IL-24 protein was generated via deletion of its signal peptide. This non-secreted protein was as effective as wild-type secreted MDA-7/IL-24 in inducing apoptosis in cancer cell lines, and displayed transformed cell specificity and localization of MDA-7/IL-24 in the Golgi/ER compartments. Based on localization as well as signal transduction pathway activation, MDA-7/IL-24 protein appears to induce ER stress that in turn induces proapoptotic events. A new reagent was generated i.e. a bacterially expressed and purified GST-MDA-7 fusion protein. We describe the properties and characteristics of this protein in this report. Treatment of breast cancer cell lines with GST-MDA-7 sensitizes both wild-type and mutant p53 expressing tumor cells to growth inhibitory and antisurvival effects of ionizing radiation. Our results indicate that mda-7/IL-24-mediated apoptosis can be triggered efficiently in the absence of protein secretion and is likely mediated by ER stress.