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Cancer Cell-Derived Clusterin Modulates the PI3K-Akt Pathway through Attenuation of IGF-1 during Serum Deprivation.| Authors: | Hakryul Jo, Yonghui Jia, Kulandayan K Subramanian, Hidenori Hattori, Hongbo R Luo | | Language: | ENG. | | Date: | 6-5-2008 | | Journal: | Molecular and cellular biology
(1098-5549)
| | Release: | Mol Cell Biol. 5 May 2008 | |
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Abstract:
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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.
| | Copyright: | Molecular and cellular biology
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. | | Full text: | | | |
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