The IGF-I receptor can alter the matrix metalloproteinase repertoire of tumor cells through transcriptional regulation of PKC-{alpha}

• Published in: Molecular endocrinology (Baltimore, Md.) Vol. 23; no. 12; p. 2013
• Main Authors: Li, Shun, Zhang, Donglei, Yang, Long, Burnier, Julia V, Wang, Ni, Lin, Rongtuan, Lee, Eunice R, Glazer, Robert I, Brodt, Pnina
• Format: Journal Article
• Language: English
• Published: United States 01.12.2009
• Subjects: Blotting, Western; Carcinogens - pharmacology; Cell Line, Tumor; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic - drug effects; Gene Expression Regulation, Neoplastic - genetics; Humans; Immunohistochemistry; Matrix Metalloproteinase 13 - metabolism; Matrix Metalloproteinase 3 - metabolism; Matrix Metalloproteinase 9 - metabolism; Matrix Metalloproteinases, Secreted - metabolism; Protein Kinase C-alpha - genetics; Protein Kinase C-alpha - metabolism; Receptor, IGF Type 1 - genetics; Receptor, IGF Type 1 - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Tetradecanoylphorbol Acetate - pharmacology
• ISSN: 1944-9917; 1944-9917
• DOI: 10.1210/me.2009-0197

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-27(IGFIR)) tumor cells. Our results show that overexpression and activation of IGF-IR reduced PKC-alpha expression, PKC activity, and downstream ERK1/2 signaling, and these effects were reversed in cells expressing kinase (Y(1131,1135,1136)F) or C-terminal (Y(1250/51)F) domain mutants of IGF-IR. This reduction was due to transcriptional down-regulation of PKC-alpha as evidenced by reduced PKC-alpha mRNA expression in a phosphatidylinositol 3-kinase-dependent manner and a blockade of PKC-alpha promoter activation as revealed by a reporter gene assay. Finally, reconstitution of PKC-alpha levels could restore MMP-9 expression levels in these cells. Collectively, these results show that IGF-IR can inhibit PKC-alpha 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.