The IGF-I receptor can alter the matrix metalloproteinase repertoire of tumor cells through transcriptional regulation of PKC-{alpha}.
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.
Department of Medicine, McGill University Health Center, Royal Victoria Hospital, Montreal, Quebec, Canada.
Shun
S
Li
Donglei
D
Zhang
Long
L
Yang
Julia V
JV
Burnier
Ni
N
Wang
Rongtuan
R
Lin
Eunice R
ER
Lee
Robert I
RI
Glazer
Pnina
P
Brodt
D015153:Blotting, Western; D002273:Carcinogens / Q000494:pharmacology; D045744:Cell Line, Tumor; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D053505:Matrix Metalloproteinases, Secreted / Q000378:metabolism*; D051571:Protein Kinase C-alpha / Q000235:genetics* / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D002273:Carcinogens; D017526:Receptor, IGF Type 1; D051571:Protein Kinase C-alpha; D053509:Matrix Metalloproteinase 13; D053505:Matrix Metalloproteinases, Secreted; D019278:Matrix Metalloproteinase 3; D020780:Matrix Metalloproteinase 9; D013755:Tetradecanoylphorbol Acetate