Induction of immunogenic cell death in radiation-resistant breast cancer stem cells by repurposing anti-alcoholism drug disulfiram

Cell Communication and Signaling

Lile He¹  Gong Zhang¹  Pan Hu¹  Xinhui Wang¹  Wei Guo¹  Albert B. DeLeo¹  Ting Sun¹  Zunwen Lin¹  Soldano Ferrone¹  Enwen Wang¹  Wei Yang²  Sneh M. Toprani² 

[1] Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital, Harvard Medical School;John B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public Health;

关键词: Breast cancer;    Stem cells;    Immunogenic cell death;    Radiation;    Disulfiram;    Copper;   

DOI  :  10.1186/s12964-019-0507-3

来源: DOAJ

【 摘 要 】

Abstract Background The current successful clinical use of agents promoting robust anti-tumor immunity in cancer patients warrants noting that radiation therapy (RT) induces immunogenic cell death (ICD) of tumor cells, which can generate anti-tumor immune responses. However, breast cancer stem cells (BCSCs) are resistant to RT and RT alone usually failed to mount an anti-tumor immune response. Methods High aldehyde dehydrogenase activity (ALDH)bright and CD44+/CD24−/ESA+ cancer cells, previously shown to have BCSC properties, were isolated from human MDA-MB-231 and UACC-812 breast cancer cell lines by flow cytometer. Flow sorted BCSCs and non-BCSCs were further tested for their characteristic of stemness by mammosphere formation assay. Induction of ICD in BCSCs vs. non-BCSCs in response to different in vitro treatments was determined by assessing cell apoptosis and a panel of damage-associated molecular pattern molecules (DAMPs) by flow and enzyme-linked immunosorbent assay (ELISA). Results We found that ionizing radiation (IR) triggered a lower level of ICD in BCSCs than non-BCSCs. We then investigated the ability of disulfiram/cooper (DSF/Cu) which is known to preferentially induce cancer stem cells (CSCs) apoptosis to enhance IR-induced ICD of BCSCs. The results indicate that DSF/Cu induced a similar extent of IDC in both BCSCs and non-BCSCs and rendered IR-resistant BCSCs as sensitive as non-BCSCs to IR-induced ICD. IR and DSF/Cu induced ICD of BCSCs could be partly reversed by pre-treatment of BCSCs with a reactive oxygen species (ROS) scavenger and XBP1s inhibitors. Conclusion DSF/Cu rendered IR-resistant BCSCs as sensitive as non-BCSCs to IR-induced ICD. Our data demonstrate the potential of IR and DSF/Cu to induce ICD in BCSCs and non-BCSCs leading to robust immune responses against not only differentiated/differentiating breast cancer cells but also BCSCs, the root cause of cancer formation, progression and metastasis. Graphical abstract

【 授权许可】

Unknown