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

Abstract

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.

• Authors: Zhaoliang Su, Ting Wang, Haitao Zhu, Pan Zhang, Rongxia Han, Yueqin Liu, Ping Ni, Huiling Shen, Wenlin Xu, Huaxi Xu
• Journal: Immunobiology (Immunobiology) Vol. 220 Issue 5 Pg. 539-44 (May 2015) ISSN: 1878-3279 [Electronic] Netherlands
• PMID: 25578401 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier GmbH. All rights reserved.

Chemical References

• Ager protein, mouse
• HMGB1 Protein
• HMGB1 protein, mouse
• RNA, Small Interfering
• Receptor for Advanced Glycation End Products

Topics

• Animals
• Apoptosis (drug effects)
• Autophagy (drug effects, genetics)
• Carcinoma, Lewis Lung (metabolism, pathology)
• Cell Line, Tumor
• Cell Nucleus (metabolism)
• Cytoplasm (metabolism)
• Feedback, Physiological
• HMGB1 Protein (genetics, metabolism)
• Lung Neoplasms (metabolism, pathology)
• MAP Kinase Signaling System
• Mice
• Protein Transport
• RNA, Small Interfering (genetics)
• Receptor for Advanced Glycation End Products (metabolism)