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

Abstract

Insulin-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.

Keywords::

• IGFBP-2
• PI3K
• AKT
• mTOR
• mRNA
• Sp1

Acknowledgements

We would like to thank Dr Lilian Amrein for the important help with immunofluorescence and members of Dr Pollak's laboratory for critical discussion.

Declaration of interest: M.M. was supported by the graduate studentship from the Weekend to End Breast Cancer of the Jewish General Hospital Foundation. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.