HMGB1 Promotes Drug Resistance in Osteosarcoma
Cette étude montre que, dans les ostéosarcomes, une protéine se liant à l'ADN, HMGB1, joue un rôle essentiel dans l'apparition d'une résistance à la chimiothérapie
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 immuno-regulatory effects in its secreted form, in the development of drug resistance in osteosarcoma. Anti-cancer agents including doxorubicin, cisplatin, and methotrexate each induced HMGB1 upregulation in human osteosarcoma cells and RNAi-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 complex that facilitates autophagic progression. Additionally, 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.