DNA damage response-initiated cytokine secretion in bone marrow stromal cells promotes chemoresistance of myeloma cells

Abstract

Acquisition of chemoresistance accounts for a major cause of chemotherapy failure for multiple myeloma (MM). Bone marrow stromal cells (BMSCs) are considered to play a pivotal role in modulating drug resistance of MM cells. However, the underlying mechanism whereby BMSCs, particularly damaged stromal cells, affects chemoresistance has not been identified yet. Here, we show exposure to doxorubicin doxorubicin (Dox) induced dramatic ATM (ataxia-telangiectasia-mutated)-dependent DNA damage response (DDR) and increased secretion of interleukin (IL)-6 in HS-5 cell line and primary BMSCs derived from healthy donors. Specifically, IL-6-containing conditioned media (CM) derived from Dox-pretreated stromal cells displayed significant protective effect on Dox-induced apoptosis of MM cells. Also, treatment of BMSCs with ATM kinase inhibitor markedly reduced IL-6 secretion and concurrently, partially reversed CM-mediated chemoresistance in myeloma cells. These data indicate that DNA-damaging drug triggers an ATM-dependent DDR in BMSCs, leading to increased cytokine secretion and resistance of myeloma cells to chemotherapy-induced apoptosis.

Keywords:

• Myeloma
• doxorubicin
• DNA damage response
• bone marrow stromal cell
• cytokine
• drug resistance

Acknowledgements

This study was supported by the Social Development Science and Technology Fund of Shaanxi Province [2015SF066 and 2016SF071] and the National Natural Science Foundation of China [81172247].

Potential conflict of interest

Disclosure forms provided by the authors are available with the full text of this article online at https://doi.org/10.1080/10428194.2017.1413188