title: 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.affiliation: The Central Laboratory, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China; Department of Immunology & Laboratory Immunology, Jiangsu University, Zhenjiang 212013, China. Electronic address: szl30@yeah.net.
authors.forename: Zhaoliang
authors.initials: Z
authors.lastname: Su
authors.affiliation: The Central Laboratory, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China; Department of Immunology & Laboratory Immunology, Jiangsu University, Zhenjiang 212013, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Immunology & Laboratory Immunology, Jiangsu University, Zhenjiang 212013, China.
authors.forename: Haitao
authors.initials: H
authors.lastname: Zhu
authors.affiliation: The Central Laboratory, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China; Department of Immunology & Laboratory Immunology, Jiangsu University, Zhenjiang 212013, China.
authors.forename: Pan
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Immunology, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Rongxia
authors.initials: R
authors.lastname: Han
authors.affiliation: The Central Laboratory, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China.
authors.forename: Yueqin
authors.initials: Y
authors.lastname: Liu
authors.affiliation: The Central Laboratory, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China; Department of Immunology & Laboratory Immunology, Jiangsu University, Zhenjiang 212013, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Ni
authors.affiliation: The Central Laboratory, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China.
authors.forename: Huiling
authors.initials: H
authors.lastname: Shen
authors.affiliation: The Central Laboratory, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China.
authors.forename: Wenlin
authors.initials: W
authors.lastname: Xu
authors.affiliation: The Central Laboratory, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China; Department of Immunology & Laboratory Immunology, Jiangsu University, Zhenjiang 212013, China.
authors.forename: Huaxi
authors.initials: H
authors.lastname: Xu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D018827:Carcinoma, Lewis Lung / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism*; D025461:Feedback, Physiological; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System; D051379:Mice; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000235:genetics; D000067759:Receptor for Advanced Glycation End Products / Q000378:metabolism*
chemical_list: C000593873:Ager protein, mouse; D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D034741:RNA, Small Interfering; D000067759:Receptor for Advanced Glycation End Products
keywords: Autophagy; HMGB1; RAGE