title: High mobility group box 1-mediated autophagy promotes neuroblastoma cell chemoresistance.
abstract: Neuroblastoma (NB) is one of the most common tumors in childhood. Unfortunately, the survival outcomes remain unsatisfactory since NB commonly develops multidrug resistance. Recent studies have demonstrated that the high mobility group box 1 (HMGB1)-mediated autophagy promotes chemoresistance in osteosarcoma, lung adenocarcinoma and ovarian cancer, but the exact molecular mechanism underlying HMGB1-mediated autophagy in NB has not been clearly defined. In the present study, we investigated the role of HMGB1 in the development of resistance to anticancer agents in NB. Anticancer agents including doxorubicin, cisplatin and etoposide each induced HMGB1 upregulation, promoted cytosolic HMGB1 translocation and the elevation of autophagic activity in human NB cells. RNA interference-mediated knockdown of HMGB1 restored the chemosensitivity of NB cells. Furthermore, mechanistic investigation revealed that HMGB1 promoted the proliferative activity and invasive potential of NB cells. HMGB1 enhanced drug resistance by inducing Beclin-1-mediated autophagy, an intracellular self-defense mechanism known to confer drug resistance. In addition, we found that HMGB1 facilitated autophagic progression and reduced oxidative stress induced by doxorubicin. Therefore, through its role as a regulator of autophagy, HMGB1 is a critical factor in the development of chemoresistance and tumorigenesis, and it may be a novel target for improving the efficacy of NB therapy.
authors.affiliation: Department of Neonatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, P.R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Neonatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, P.R. China.
authors.forename: Huiping
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Neonatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, P.R. China.
authors.forename: Min
authors.initials: M
authors.lastname: Sun
authors.affiliation: Department of Neonatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, P.R. China.
authors.forename: Zhanghua
authors.initials: Z
authors.lastname: Yin
authors.affiliation: Department of Neonatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, P.R. China.
authors.forename: Jihong
authors.initials: J
authors.lastname: Qian
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D001343:Autophagy / Q000235:genetics*; D000071186:Beclin-1; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005047:Etoposide / Q000008:administration & dosage; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D024243:HMGB1 Protein / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D009447:Neuroblastoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects
chemical_list: D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D024243:HMGB1 Protein; D008565:Membrane Proteins; D005047:Etoposide; D004317:Doxorubicin; D002945:Cisplatin