Secretory Clusterin Is a Marker of Tumor Progression Regulated by IGF-1 and Wnt Signaling Pathways

Secretory clusterin (sCLU) is a pro-survival factor that can be induced by cellular stress, including ionizing radiation (IR), many cytotoxic agents, and during cellular replicative or low doses of stress-induced senescence. sCLU expression changes with tumor stage and grade in various types of cancer. Previously our laboratory found that sCLU was induced by IR through activation of the IGF-IR/Src/MEK/Erk/Egr-1 pathway. APC loss in Min-/- mice was also linked to elevated sCLU expression, especially in human colon cancer. We now find that Wnt signaling can cross talk with IGF-1 signaling to regulate sCLU expression. The cross talk between the IGF-1 and Wnt signaling pathways is very complex, not only because they share many components but also because they are delicately regulated by time, dose, and cell type. Both positive and negative feedback regulation loops regulate sCLU expression. Understanding these complicated signaling pathways will be essential for delineating the roles of Wnt, IGF-1, and sCLU expression in tumor progression, aging, and cancer, as well as in heart and Alzheimer's diseases aberrant where sCLU expression has been implicated.