PMID- 33762577
OWN - NLM
STAT- MEDLINE
DCOM- 20211013
LR  - 20211013
IS  - 2041-4889 (Electronic)
VI  - 12
IP  - 4
DP  - 2021 Mar 24
TI  - Oleandrin, a cardiac glycoside, induces immunogenic cell death via the 
      PERK/elF2alpha/ATF4/CHOP pathway in breast cancer.
PG  - 314
LID - 10.1038/s41419-021-03605-y [doi]
LID - 314
AB  - Chemotherapeutic agents have been linked to immunogenic cell death (ICD) 
      induction that is capable of augmenting anti-tumor immune surveillance. The 
      cardiac glycoside oleandrin, which inhibits Na(+)/K(+)-ATPase pump (NKP), has 
      been shown to suppress breast cancer growth via inducing apoptosis. In the 
      present study, we showed that oleandrin treatment triggered breast cancer cell 
      ICD by inducing calreticulin (CRT) exposure on cell surface and the release of 
      high-mobility group protein B1 (HMGB1), heat shock protein 70/90 (HSP70/90), and 
      adenosine triphosphate (ATP). The maturation and activation of dendritic cells 
      (DCs) were increased by co-culturing with the oleandrin-treated cancer cells, 
      which subsequently enhanced CD8(+) T cell cytotoxicity. Murine breast cancer cell 
      line EMT6 was engrafted into BALB/c mice, and tumor-bearing mice were 
      administered with oleandrin intraperitoneally every day. Oleandrin inhibited 
      tumor growth and increased tumor infiltrating lymphocytes including DCs and T 
      cells. Furthermore, the differential mRNA expression incurred by oleandrin was 
      investigated by mRNA sequencing and subsequently confirmed by quantitative 
      real-time polymerase chain reaction (qRT-PCR) and western blotting. 
      Mechanistically, oleandrin induced endoplasmic reticulum (ER) stress-associated, 
      caspase-independent ICD mainly through PERK/elF2alpha/ATF4/CHOP pathway. 
      Pharmacological and genetic inhibition of protein kinase R-like ER kinase (PERK) 
      suppressed oleandrin-triggered ICD. Taken together, our findings showed that 
      oleandrin triggered ER stress and induced ICD-mediated immune destruction of 
      breast cancer cells. Oleandrin combined with immune checkpoint inhibitors might 
      improve the efficacy of immunotherapy.
FAU - Li, Xiaoxi
AU  - Li X
AD  - Central Laboratory, Cancer Hospital of China Medical University, Liaoning Cancer 
      Hospital & Institute, Shenyang, Liaoning, 110042, People's Republic of China.
FAU - Zheng, Jian
AU  - Zheng J
AD  - Department of Thoracic Cancer, Cancer Hospital of China Medical University, 
      Liaoning Cancer Hospital & Institute, Shenyang, Liaoning, 110042, People's 
      Republic of China.
FAU - Chen, Shi
AU  - Chen S
AD  - Central Laboratory, Cancer Hospital of China Medical University, Liaoning Cancer 
      Hospital & Institute, Shenyang, Liaoning, 110042, People's Republic of China.
FAU - Meng, Fan-Dong
AU  - Meng FD
AD  - Molecular Oncology Laboratory of Cancer Research Institute, The First Affiliated 
      Hospital of China Medical University, Shenyang, Liaoning, 110001, People's 
      Republic of China.
FAU - Ning, Jing
AU  - Ning J
AD  - Department of General Medicine (VIP ward) & Department of Tumor Supportive and 
      Palliative Medicine, Cancer Hospital of China Medical University, Liaoning Cancer 
      Hospital & Institute, Shenyang, Liaoning, 110042, People's Republic of China.
FAU - Sun, Shu-Lan
AU  - Sun SL
AUID- ORCID: 0000-0002-7624-1797
AD  - Central Laboratory, Cancer Hospital of China Medical University, Liaoning Cancer 
      Hospital & Institute, Shenyang, Liaoning, 110042, People's Republic of China. 
      sunshulan@cancerhosp-ln-cmu.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210324
PL  - England
TA  - Cell Death Dis
JT  - Cell death & disease
JID - 101524092
RN  - 0 (Atf4 protein, mouse)
RN  - 0 (Cardenolides)
RN  - 0 (Cardiac Glycosides)
RN  - 145891-90-3 (Activating Transcription Factor 4)
RN  - II95UDU7I4 (oleandrin)
SB  - IM
MH  - Activating Transcription Factor 4/*metabolism
MH  - Animals
MH  - Breast Neoplasms/*drug therapy/pathology
MH  - Cardenolides/pharmacology/*therapeutic use
MH  - Cardiac Glycosides/pharmacology/*therapeutic use
MH  - Cell Line, Tumor
MH  - Disease Models, Animal
MH  - Female
MH  - Humans
MH  - Immunogenic Cell Death/*genetics
MH  - Mice
PMC - PMC7990929
COIS- The authors declare no competing interests.
EDAT- 2021/03/26 06:00
MHDA- 2021/10/14 06:00
PMCR- 2021/03/24
CRDT- 2021/03/25 05:56
PHST- 2020/12/23 00:00 [received]
PHST- 2021/03/10 00:00 [accepted]
PHST- 2021/03/08 00:00 [revised]
PHST- 2021/03/25 05:56 [entrez]
PHST- 2021/03/26 06:00 [pubmed]
PHST- 2021/10/14 06:00 [medline]
PHST- 2021/03/24 00:00 [pmc-release]
AID - 10.1038/s41419-021-03605-y [pii]
AID - 3605 [pii]
AID - 10.1038/s41419-021-03605-y [doi]
PST - epublish
SO  - Cell Death Dis. 2021 Mar 24;12(4):314. doi: 10.1038/s41419-021-03605-y.