An investigation of the biological activities of rainbow trout Ela4-peptide of pro-IGF-I in human cancer cells

E-peptides are the C-terminal domain of pro-IGFs, which are proteolytically cleaved from the pro-IGFs and subsequently co-secreted with mature IGFs. E-peptide was thought to be biological inactive until recently. Although, many biological activities have been shown to be associated with E-peptides in both non-transformed and transformed cells in recent years, very little is known about the mode of action of these peptides at the molecular level. ^ The specific goals of this thesis are to characterize the biological activities and to explore the potential molecular mechanism of rainbow trout Ela4-peptide using a well-characterized human breast cancer cell line, MDA-MB-231, as the cell model of the study. Results of these studies reveal that trout Ela4-peptide possesses activities in inducing unique cell morphological change, promoting cell attachment, and reducing cell invasion on MDA-MB-231 cells. The mechanism of Ela4-peptide in promoting cell attachment is likely mediated via (1) the binding of Ela4-peptide to the integrin receptors (α2 and β1) and (2) the induction of adhesion molecule and adhesion cell membrane receptor (fibronectin 1 and laminin receptor). The regulation of fibronectin 1 gene expression by Ela4-peptide is potentially mediated via the FAK/MAPK pathways. Ela4 peptide is also believed to reduce invasion by (1) suppressing the expression of proteases, uPA and tPA via the FAK/MAPK pathways and (2) promoting cell adhesion. Most anti-invasive, anti-metastatic agents function in either enhancing cell attachment or reducing the production of proteases. Since Ela4-peptide possesses both functions, it perhaps can be used as an effective anti-invasive, anti-metastatic agent. The information obtained from this dissertation has provided the foundation for understanding the biological activities as well as molecular mechanism of Ela4-peptide action. Further studies conducted in this system may lead to the development of a new generation of therapeutic agents for the management of human cancers.