Cancer cell-derived clusterin modulates the phosphatidylinositol 3'-kinase-Akt pathway through attenuation of insulin-like growth factor 1 during serum deprivation.

作者:	Hakryul Jo, Yonghui Jia, Kulandayan K Subramanian, Hidenori Hattori, Hongbo R Luo
语言:	Eng.
日期:	16-06-2008
学报:	Molecular and cellular biology (1098-5549)
发行:	Mol Cell Biol. 2008 Jul;28(13):4285-99
摘要:	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.
版权:	Molecular and cellular biology Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA.
全文:	Molecular and cellular biology (DOI) EBSCO - HTML (需要捐款) HighWire Press - HTML (需要捐款)