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Molecular and Cellular Biology, July 2008, p. 4285-4299, Vol. 28, No. 13
0270-7306/08/$08.00+0     doi:10.1128/MCB.01240-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Cancer Cell-Derived Clusterin Modulates the Phosphatidylinositol 3'-Kinase-Akt Pathway through Attenuation of Insulin-Like Growth Factor 1 during Serum Deprivation ^,

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

Received 11 July 2007/ Returned for modification 8 October 2007/ Accepted 2 May 2008

Cancer cells in their respective microenvironments must endure various growth-constraining 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 phosphatidylinositol 3'-kinase (PI3K)-Akt pathway under serum deprivation stress. Through the use of biochemical purification, we reveal that cancer cell-secreted insulin-like growth factor 1 (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 the IGF-1 receptor and hence negatively regulates the PI3K-Akt pathway during serum deprivation. This inhibitory function of clusterin appears to prefer IGF-1, as it fails to exert any effects on epidermal growth factor signaling. We demonstrate furthermore that the constitutive activation of oncogenic signaling downstream of IGF-1 confers insensitivity to the inhibitory effects of clusterin. Thus, the interplay between cancer cell-derived clusterin and IGF-1 may dictate the outcome of cell growth and dormancy during tumorigenic progression.

Published ahead of print on 5 May 2008.

Supplemental material for this article may be found at http://mcb.asm.org/.