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language
eng
Author
Inao, Touko Department of Immunology, Shimane University Faculty of Medicine, Izumo, Japan / Department of Breast Surgery, Osaka Breast Clinic, Osaka, Japan
Irna Diyana Kartika Department of Immunology, Shimane University Faculty of Medicine, Izumo, Japan
Okimoto, Tamio Division of Medical Oncology and Respiratory Medicine, Department of Internal Medicine, Shimane University Faculty of Medicine, Izumo, Japan
Shiba, Eiichi Department of Breast Surgery, Osaka Breast Clinic, Osaka, Japan.
Description
Senescence is a state of growth arrest induced not only in normal cells but also in cancer cells by aging or stress, which triggers DNA damage. Despite growth suppression, senescent cancer cells promote tumor formation and recurrence by producing cytokines and growth factors; this state is designated as the senescence-associated secretory phenotype. In this study, we examined the susceptibility of senescent human breast cancer cells to immune cell-mediated cytotoxicity. Doxorubicin (DXR) treatment induced senescence in 2 human breast cancer cell lines, MDA-MB-231 and BT-549, with the induction of γH2AX expression and increased expression of p21 or p16. Treatment with DXR also induced the expression of senescence-associated β-galactosidase and promoted the production of pro-inflammatory cytokines. Importantly, DXR-treated senescent MDA-MB-231 cells showed increased sensitivity to 2 types of immune cell-mediated cytotoxicity: cytotoxicity of activated CD4+ T cells and Ab-dependent cellular cytotoxicity by natural killer cells. This increased sensitivity to cytotoxicity was partially dependent on tumor necrosis factor-related apoptosis-inducing ligand and perforin, respectively. This increased sensitivity was not observed following treatment with the senescence-inducing cyclin-dependent kinase-4/6 inhibitor, abemaciclib. In addition, treatment with DXR, but not abemaciclib, decreased the expression of antiapoptotic proteins in cancer cells. These results indicated that DXR and abemaciclib induced senescence in breast cancer cells, but that they differed in their sensitivity to immune cell-mediated cytotoxicity. These findings could provide an indication for combining anticancer immunotherapy with chemotherapeutic drugs or molecular targeting drugs.
Subject
abemaciclib
breast cancer
cytotoxicity
doxorubicin
senescence
Journal Title
Cancer science
Volume
110
Issue
9
Start Page
2690
End Page
2699
ISSN
1347-9032
ISSN(Online)
1349-7006
Published Date
2019-07-23
DOI
Publisher
the Japanese Cancer Association
NII Type
Journal Article
Format
PDF
Text Version
出版社版
Gyoseki ID
e38108
OAI-PMH Set
Faculty of Medicine