Cancer Cell-Derived Clusterin Modulates the PI3K-Akt Pathway through Attenuation of IGF-1 during Serum Deprivation

Department of Pathology, Harvard Medical School; Dana-Farber/Harvard Cancer Center; Department of Lab Medicine, The Stem Cell program, Joint Program in Transfusion Medicine, Children's Hospital Boston

^* To whom correspondence should be addressed. Email: Hongbo.Luo{at}childrens.harvard.edu.

	Abstract

Cancer cells in their respective microenvironment must endure various growth constraint stresses. Under these conditions, the cancer cell-derived factors are thought to modulate the signaling pathways between cell growth and dormancy. Here we describe a cancer cell-derived regulatory system that modulates the PI3K-Akt pathway under serum deprivation stress. Through biochemical purification, we reveal that cancer cell-secreted IGF-1 and Clusterin, an extracellular stress protein, constitute this regulatory system. We show that secreted Clusterin associates with IGF-1 and inhibits its binding to IGF-1 receptor, hence negatively regulating the PI3K-Akt pathway during serum deprivation. This inhibitory function of Clusterin appears to be preferential to IGF-1 as it fails to exert any effects on EGF signaling. We further demonstrate that constitutive activation of oncogenic signaling downstream of IGF-1 confers the insensitivity to inhibitory effects of Clusterin. Thus, the interplays between cancer cell-derived Clusterin and IGF-1 may dictate the outcome of cell growth and dormancy during tumorigenic progression.