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.