HMGB1 promotes drug resistance in osteosarcoma

Jun Huang, Jiangdong Ni, Ke Liu, Yan Yu, Min Xie, Rui Kang, Philip Vernon, Lizhi Cao, Daolin Tang

Research output: Contribution to journalArticlepeer-review

181 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)230-238
Number of pages9
JournalCancer research
Volume72
Issue number1
DOIs
StatePublished - Jan 1 2012
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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