HMGB1 modulates Lewis cell autophagy and promotes cell survival via RAGE-HMGB1-Erk1/2 positive feedback during nutrient depletion.

Autophagy is a self-digesting mechanism responsible for the removal of long-lived proteins and damaged organelles by lysosomes. It also allows cells to survive during nutrient depletion and/or in the absence of growth factors. High-mobility group protein 1 (HMGB1) is a highly-conserved nuclear protein that has been associated with cell autophagy; however, the mechanisms responsible for this role remain unclear. Many reports have demonstrated that autophagy represents a survival strategy for tumor cells during nutrient depletion, oxidative stress and DNA damage. In the present study, we explored the mechanisms whereby HMGB1 regulates tumor cell autophagy during nutrient depletion (the cells were cultured in Hank's balanced salt solution, HBSS). HMGB1 expression in Lewis cells increased and the protein was shuttled from the nucleus to the cytoplasm and was secreted, coincident with up-regulation of autophagy. Prevention of HMGB1 binding to the receptor for advanced glycation end products (RAGE) or knock-down of HMGB1 expression led to inhibition of autophagy and increased apoptosis. These results demonstrated a positive feedback pathway whereby starvation of Lewis cells promoted HMGB1 secretion, allowing cells to survive by regulating autophagy via a RAGE-HMGB1-extracellular signal-regulated kinase1/2-dependent pathway. These results also implicate HMGB1 as a potential risk factor for cancer growth and metastasis.

[Prediction and modification analysis of low-affinity HLA-A*0201 restricted CTL epitopes derived from HIV-1 pol antigen].

AIM: To screen the possible HLA-A*0201 restricted low-affinity CTL epitopes derived from HIV-1 pol antigen and to predict and identify the possible change of the affinity between epitope and the HLA-A*0201 molecule when the epitope is modified. METHODS: HLA-A*0201 restricted low-affinity CTL epitopes were predicted by CTL epitope prediction software based on super motif, proteasome cleavage probability, HLA affinity and so on. The candidates were modified acid substitution and analyzed by computer. T2 cells were used to determine the peptide by amino binding affinity and HLA-A*0201-peptide complex stability. RESULTS: Among the three predicted peptides by softer ware, YVSLSFPQI (pol52-60Y1), YVSQIIEQL pol(673-681Y1), YIQKETWEA(pol548-556Y1)could bind to HLA-A*0201 with high affinity, and the dissociation time of 50% HLA-A*0201 peptide complex was over to 8 h. CONCLUSION: Our results suggest that the three predicted peptides, as modification, might be HLA-A*0201 restricted CTL epitopes.