IGFBP-2 expression in MCF-7 cells is regulated by the PI3K/AKT/mTOR pathway through Sp1-induced increase in transcription

Matei Mireutaa, Andrew Darnela & Michael Pollak*aa Departments of Medicine and Oncology, Lady Davis Institute for Medical Research, Montreal SMBD Jewish General Hospital, and McGill University, Montreal, Quebec, CanadaH3T 1E2,Correspondence: M. Pollak, Departments of Medicine and Oncology, Jewish General Hospital, 3755 Chemin Cote Ste-Catherine, Montreal, Quebec, Canada H3T 1E2. Tel: 514 340 8222. Ext. 5530. Fax: 514 340 8600. E-mail: michael.pollak@mcgill.caInsulin-like growth factor binding protein 2 (IGFBP-2) has been implicated in the pathophysiology of neoplasia. The PI3K/AKT/mTOR pathway has recently been shown to be a predominant regulator of IGFBP-2 at the protein level in MCF-7 breast cancer cells. However, there are gaps in knowledge with respect to the molecular mechanisms that underlie this regulation. Here, we show that the PI3K/AKT/mTOR pathway regulates IGFBP-2 protein levels by modulating IGFBP-2 mRNA abundance in MCF-7 cells. This change is achieved by regulating transcription through a critical region present in the first 200 bp upstream of the transcription initiation site where Sp1 transcription factor binds and drives transcription. IGF-1 treatment leads to increased nuclear abundance of Sp1 and increased IGFBP-2 mRNA and protein levels. Rapamycin and LY294002 induce a decline in Sp1 nuclear abundance and IGFBP-2 mRNA and protein levels. This work provides a mechanistic explanation for the observed effects of the PI3K/AKT/mTOR pathway on IGFBP-2 levels in MCF-7 cells.