Induction of immunogenic cell death in radiation-resistant breast cancer stem cells by repurposing anti-alcoholism drug disulfiram (vol 18, 36, 2020)

被引：2

作者：

Sun, Ting ^{[1
,2
]}

Yang, Wei ^{[3
,4
,5
]}

Toprani, Sneh M. ^{[3
]}

Guo, Wei ^{[1
]}

He, Lile ^{[1
]}

DeLeo, Albert B. ^{[1
]}

Ferrone, Soldano ^{[1
,6
]}

Zhang, Gong ^{[1
]}

Wang, Enwen ^{[1
]}

Lin, Zunwen ^{[1
]}

Hu, Pan ^{[1
]}

Wang, Xinhui ^{[1
]}

机构：

[1] Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Div Surg Oncol, Boston, MA 02115 USA

[2] Soochow Univ, Affiliated Hosp 1, Neurosurg & Brain & Nerve Res Lab, Suzhou, Jiangsu, Peoples R China

[3] Harvard TH Chan Sch Publ Hlth, John B Little Ctr Radiat Sci, Boston, MA USA

[4] Soochow Univ, State Key Lab Radiat Med & Protect, Sch Radiat Med & Protect, Suzhou, Peoples R China

[5] Soochow Univ, Jiangsu Higher Educ Inst, Collaborat Innovat Ctr Radiat Med, Suzhou, Peoples R China

[6] Harvard Med Sch, Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02115 USA

来源：

CELL COMMUNICATION AND SIGNALING | 2020年 / 18卷 / 01期

关键词：

Breast cancer; Copper; Disulfiram; Immunogenic cell death; IRE1α; Radiation; Reactive oxygen species; Signaling pathway; Stem cells; XBP1s;

D O I：

10.1186/s12964-020-00567-0

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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: [Figure not available: see fulltext.] © 2020 The Author(s).

引用

页数：1