N-terminal gelsolin fragment potentiates TRAIL mediated death in resistant hepatoma cells

Abstract

TNF-α related apoptosis-inducing ligand (TRAIL) selectively kills tumor cells, without damaging normal cells. TRAIL receptors facilitate induction of apoptosis for selective elimination of malignant cells. However, some cancer cells have developed resistances to TRAIL which limits anticancer potential. Gelsolin, a multifunctional actin-binding protein, mediates cell death involving the TRAIL receptors in the hepatic stellate cell line, LX2. Here, we have shown that conditioned medium (CM) containing gelsolin fragments or an N-terminal gelsolin fragment (amino acid residues 1–70) in the presence of TRAIL impairs cell viability of TRAIL resistant transformed human hepatocytes (HepG2). Cell growth regulation by CM and TRAIL was associated with the modulation of p53/Mdm2, Erk and Akt phosphorylation status. The use of N-terminal gelsolin peptide1–70 alone or in combination with TRAIL, induced inhibition of Akt phosphorylation and key survival factors, Mdm2 and Survivin. Treatment of cells with an Akt activator SC79 or p53 siRNA reduced the effects of the N-terminal gelsolin fragment and TRAIL. Together, our study suggests that the N-terminal gelsolin fragment enhances TRAIL-induced loss of cell viability by inhibiting phosphorylation of Akt and promoting p53 function, effecting cell survival.