Signalling pathways involved in antiproliferative effects of IGFBP-3: a review

Insulin-like growth factor binding protein-3 (IGFBP-3), the major circulati ng carrier protein for IGFs, is also active in the cellular environment as a potent antiproliferative agent. It appears to function both by cell cycle blockade and the induction of apoptosis. Transfection of p53 negative T47D breast cancer cells to express IGFBP-3 leads to induction of the apoptotic protein bar and an increase in sensitivity to ionising radiation. IGFBP-3 can be transported to the nucleus by an importin beta mediated mechanism, w here it has been shown to interact with the retinoid X receptor a and possi bly other nuclear elements. Expression of oncogenic ras is associated with resistance to exogenous IGFBP-3, the effect being reversible by inhibition of mitogen activated protein (MAP) kinase phosphorylation. IGFBP-3 antiprol iferative signalling appears to require an active transforming growth facto r beta (TGF-beta) signalling pathway, and IGFBP-3 stimulates phosphorylatio n of the TGF-beta signalling intermediates Smad2 and Smad3. These recent fi ndings all point to a complex intracellular mode of action of IGFBP-3, whic h will need to be better understood if anti-cancer treatments are to take a dvantage of the antiproliferative activity of IGFBP-3.