N-terminal gelsolin fragment potentiates TRAIL mediated death in resistant hepatoma cells
Keith Meyer1, Young-Chan Kwon1, Ratna B Ray2
1Departments of Internal Medicine and Pathology, Saint Louis University, Missouri, USA.
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.
Insights
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) shows promise against cancer. A gelsolin fragment enhances TRAIL
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in tumor cells.
- Cancer cells can develop resistance to TRAIL, limiting its therapeutic potential.
- Gelsolin fragments are implicated in mediating cell death pathways.
Purpose of the Study:
- To investigate the potential of gelsolin fragments to overcome TRAIL resistance in cancer cells.
- To elucidate the molecular mechanisms underlying the combined effects of gelsolin fragments and TRAIL.
Main Methods:
- Utilized conditioned medium (CM) with gelsolin fragments and TRAIL on TRAIL-resistant human hepatocytes (HepG2).
- Analyzed modulation of key signaling pathways including p53/Mdm2, Erk, and Akt phosphorylation.
- Assessed the impact of N-terminal gelsolin peptide (1-70) on cell viability and survival factors.
- Investigated the role of Akt and p53 using an Akt activator (SC79) and p53 siRNA.
Main Results:
- N-terminal gelsolin fragment (1-70) combined with TRAIL impaired viability in TRAIL-resistant HepG2 cells.
- The combination therapy modulated p53/Mdm2, Erk, and Akt phosphorylation.
- N-terminal gelsolin peptide inhibited Akt phosphorylation and survival factors Mdm2 and Survivin.
- Akt activation or p53 knockdown partially reversed the effects of the gelsolin fragment and TRAIL.
Conclusions:
- The N-terminal gelsolin fragment enhances TRAIL-induced cancer cell death.
- This enhancement is mediated by inhibiting Akt phosphorylation and promoting p53-dependent cell death.
- Gelsolin fragments represent a potential strategy to overcome TRAIL resistance in cancer therapy.
