Multiple myeloma is the second most frequently diagnosed hematologic malignancy in the United States after non-Hodgkin lymphoma. Unfortunately, multiple myeloma remains incurable, and virtually all patients eventually relapse with disease that is typically more resistant to therapy than in prior lines of treatment, for which the underlying molecular mechanisms remain unclear. In this study, we showed that high-mobility group box 1 (HMGB1), the best characterized damage-associated molecular pattern, in the development of chemotherapy resistance in multiple myeloma. To examine its potential role of chemotherapy resistance in myeloma, we detected protein expression of HMGB1 treated with anticancer chemotherapy agent doxorubicin and observed that HMGB1 was upregulated by different concentrations of doxorubicin in myeloma cells. Chemosensitivity assay was performed with RPMI 8226 and U266 cells with knockdown/overexpression of HMGB1 and treated with doxorubicin, and cells were detected for their viability by WST-1 assay after 72 hr. Consistently, shRNA interference-mediated knockdown of HMGB1 cells exhibited significant sensitized to doxorubicin treatment compared to non-targeting shRNA cells, and HMGB1-overexpressing cells significantly resistance to doxorubicin. Furthermore, studies in xenograft models showed that shRNA of HMGB1 also sensitized the chemosensitivity of multiple myeloma cells in vivo. At the molecular level, mechanistic investigation showed that shRNA of HMGB1 decreased autophagy, which is an intracellular self-defense mechanism to drug resistance, by inhibition of the autophagic marker microtubule-associated protein light chain 3-II and increasing of sequestosome 1 (p62) and autophagosome formation. Finally, we found that HMGB1 regulated autophagy and apoptosis by binding to p53 and Beclin1, and p53 is a negative regulator of the HMGB1/Beclin1 complex. Taken together, these data support the hypothesis that HMGB1 modulates chemotherapy resistance in myeloma through effects on the pathway of autophagy and apoptosis, as well as a target for strategies to aim at laying the foundation for further clinical studies, and overcome chemoresistance in multiple myeloma.

Note: This abstract was not presented at the meeting.

Citation Format: Xingding Zhang, Lin Qi, Lin Yang. HMGB1 regulates autophagy and apoptosis to promote chemotherapy resistance in multiple myeloma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 680. doi:10.1158/1538-7445.AM2014-680