FIGURE 4.

IGF-Independent involvement of IGFBP-3 in cell survival pathways. (A) IGFBP-3 potentiates cell survival through the inhibition of ceramide (inducer of apoptosis) synthesis by the inactivation of sphingomyelinase and (B) by the activation of sphingosine kinase that results in the formation of sphingosine 1 kinase from sphingosine. While sphingosine can induce apoptosis, sphingosine 1 phosphate can potentiate cell survival. (C) Sphingosine 1 phosphate is secreted and can bind with its receptor, which can (D) transactivate EGFR, growth survival receptor. (E) Due to radiation, through the lipid rafts IGFBP-3 and EGFR are internalized into the cell and translocated into the nucleus, where EGFR-IGFBP-3 can complex with DNA-PK (DNA-protein kinase) facilitating DNA double stranded break repair through non-homologous end joining (NHEJ). DNA-PK complex includes Ku70 and Ku80 that encircles 20 bp DNA and kinase, which is the catalytic subunit, DNA-PKcs.