title: HMGB1 promotes drug resistance in osteosarcoma.
abstract: Osteosarcoma is the most commonly occurring bone cancer in children and adolescents. Unfortunately, treatment failures are common due to the development of chemoresistance, for which the underlying molecular mechanisms remain unclear. In this study, we implicate the DNA-binding protein HMGB1, which also exerts immunoregulatory effects in its secreted form, in the development of drug resistance in osteosarcoma. Anticancer agents including doxorubicin, cisplatin, and methotrexate each induced HMGB1 upregulation in human osteosarcoma cells, and RNA interference-mediated knockdown of HMGB1 restored the chemosensitivity of osteosarcoma cells in vivo and in vitro. Mechanistic investigation revealed that HMGB1 increased drug resistance by inducing autophagy, an intracellular self-defense mechanism known to confer drug resistance. We found that HMGB1 bound to the autophagy regulator Beclin1 and regulated the formation of the Beclin1-PI3KC3 [PI3KC3, phosphatidylinositol 3-kinase class 3] complex that facilitates autophagic progression. In addition, we found that interaction between HMGB1 and Beclin1 relied upon the autophagic complex ULK1-mAtg13-FIP200. Therefore, through its role as a regulator of autophagy, HMGB1 is a critical factor in the development of chemoresistance, and it offers a novel target for improving osteosarcoma therapy.
authors.affiliation: Departments of Orthopaedics, The Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China.
authors.forename: Jun
authors.initials: J
authors.lastname: Huang
authors.forename: Jiangdong
authors.initials: J
authors.lastname: Ni
authors.forename: Ke
authors.initials: K
authors.lastname: Liu
authors.forename: Yan
authors.initials: Y
authors.lastname: Yu
authors.forename: Min
authors.initials: M
authors.lastname: Xie
authors.forename: Rui
authors.initials: R
authors.lastname: Kang
authors.forename: Philip
authors.initials: P
authors.lastname: Vernon
authors.forename: Lizhi
authors.initials: L
authors.lastname: Cao
authors.forename: Daolin
authors.initials: D
authors.lastname: Tang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects; D001483:Base Sequence; D045744:Cell Line, Tumor; D017931:DNA Primers; D019008:Drug Resistance, Neoplasm; D024243:HMGB1 Protein / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D051379:Mice; D012516:Osteosarcoma / Q000473:pathology*; D034622:RNA Interference; D060888:Real-Time Polymerase Chain Reaction; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D017931:DNA Primers; D024243:HMGB1 Protein