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Molecular Endocrinology

Year: 2009  |  Volume: 23  |  Issue: 12  |  Page No.: 2013 - 2025

The IGF-I Receptor Can Alter the Matrix Metalloproteinase Repertoire of Tumor Cells through Transcriptional Regulation of PKC-{alpha}

S Li, D Zhang, L Yang, J. V Burnier, N Wang, R Lin, E. R Lee, R. I Glazer and P. Brodt

Abstract

The IGF-I receptor (IGF-IR) was identified as a tumor progression factor, but its role in invasion and metastasis has been the subject of some controversy. Previously we reported that in murine lung carcinoma M-27 cells, overexpression of IGF-IR increased the synthesis and activation of matrix metalloproteinase (MMP)-2 via Akt/phosphatidylinositol 3-kinase signaling. In contrast, we show here that in these and other cells, IGF-IR overexpression reduced the constitutive and phorbol 12-myristate 13-acetate (PMA)-inducible expression of three protein kinase C (PKC)-regulated metalloproteinases, MMP-3, MMP-9, and MMP-13, in cultured cells as well as in vivo in sc tumors. To elucidate the underlying mechanism, we analyzed the effect of IGF-IR on PKC expression and activity using wild-type and IGF-IR-overexpressing (M-27IGFIR) tumor cells. Our results show that overexpression and activation of IGF-IR reduced PKC- expression, PKC activity, and downstream ERK1/2 signaling, and these effects were reversed in cells expressing kinase (Y1131,1135,1136F) or C-terminal (Y1250/51F) domain mutants of IGF-IR. This reduction was due to transcriptional down-regulation of PKC- as evidenced by reduced PKC- mRNA expression in a phosphatidylinositol 3-kinase-dependent manner and a blockade of PKC- promoter activation as revealed by a reporter gene assay. Finally, reconstitution of PKC- levels could restore MMP-9 expression levels in these cells. Collectively, these results show that IGF-IR can inhibit PKC- gene transcription and thereby block the synthesis of PMA-regulated MMPs, suggesting that within the same cells, IGF-IR can act as both a positive and negative regulator of MMP expression and function.

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