PMID- 29620207
OWN - NLM
STAT- MEDLINE
DCOM- 20180926
LR  - 20190110
IS  - 1791-3004 (Electronic)
IS  - 1791-2997 (Print)
IS  - 1791-2997 (Linking)
VI  - 17
IP  - 6
DP  - 2018 Jun
TI  - Calotropin regulates the apoptosis of non‑small cell cancer by regulating the 
      cytotoxic T‑lymphocyte associated antigen 4‑mediated TGF‑beta/ERK signaling pathway.
PG  - 7683-7691
LID - 10.3892/mmr.2018.8853 [doi]
AB  - Non‑small‑cell lung cancer (NSCLC) is one of the most common malignancies that is 
      responsible for a high level of cancer‑associated mortalities worldwide. Previous 
      evidence has shown that Calotropin is an upstream activator of protein kinase B, 
      which can further inhibit the growth and promote the apoptosis of NSCLC cells. In 
      the present study, the efficacy of Calotropin on growth, aggressiveness and 
      apoptosis of NSCLC cells was investigated, as well as the potential underlying 
      mechanism. The results demonstrated that Calotropin inhibited H358 cell growth, 
      migration and invasion. Flow cytometry assay showed that Calotropin promoted the 
      apoptosis of H358 cells in vitro. Western blot analysis demonstrated that 
      Calotropin inhibited fibronectin (FN), Vimentin (VIM) and E‑cadherin (Eca) 
      protein expression levels in H358 cells in vitro. In addition, Calotropin 
      treatment upregulated pro‑apoptosis gene expression, including caspase‑3, 
      caspase‑8 and apoptotic protease activating factor‑1, and downregulated 
      anti‑apoptosis gene expression, including P53, B‑cell lymphoma (Bcl) 2 and 
      Bcl‑2‑like protein 2 in H358 cells. The results also revealed that the expression 
      levels of cytotoxic T‑lymphocyte associated antigen 4 (CTLA‑4) were decreased by 
      Calotropin treatment in H358 cells. Analyses of the underlying mechanism 
      indicated that Calotropin inhibited transforming growth factor‑beta (TGF‑beta) and 
      extracellular signal‑regulated kinase (ERK) expression. Overexpression of CTLA‑4 
      inhibited Calotropin‑mediated downregulation of TGF‑beta and ERK expression in H358 
      cells. In vivo assay revealed that Calotropin administration significantly 
      inhibited tumor growth and prolonged animal survival over the 120‑day observation 
      period. Immunohistochemistry demonstrated that the number of apoptotic cells 
      increased and the expression levels of CTLA‑4 were decreased in the 
      Calotropin‑treated tumor group when compared with control. In addition, the 
      expression levels of TGF‑beta and ERK were downregulated in the Calotropin‑treated 
      tumor group compared with control. In conclusion, the results of the present 
      study indicated that Calotropin administration regulated NSCLC apoptosis by 
      downregulating the CTLA‑4‑mediated TGF‑beta/ERK signaling pathway, suggesting that 
      Calotropin may be a potential anti‑cancer agent for the treatment of NSCLC.
FAU - Tian, Lu
AU  - Tian L
AD  - Department of Respiratory Medicine, The Fourth People's Hospital of Guiyang, 
      Guiyang, Guizhou 550002, P.R. China.
FAU - Xie, Xiao-Hong
AU  - Xie XH
AD  - Department of Respiratory Diseases, The First Affiliated Hospital of Guangzhou 
      Medical University, Guangzhou Institute of Respiratory Disease, Guangzhou, 
      Guangdong 510120, P.R. China.
FAU - Zhu, Ze-Hao
AU  - Zhu ZH
AD  - Department of Respiratory Medicine, The Affiliated Zhoushan Hospital of Wenzhou 
      Medical University, Zhoushan, Zhejiang 316000, P.R. China.
LA  - eng
PT  - Journal Article
DEP - 20180405
PL  - Greece
TA  - Mol Med Rep
JT  - Molecular medicine reports
JID - 101475259
RN  - 0 (CTLA-4 Antigen)
RN  - 0 (CTLA4 protein, human)
RN  - 0 (Cardenolides)
RN  - 0 (Transforming Growth Factor beta)
RN  - 3XK21U1BZS (calotropin)
SB  - IM
MH  - Animals
MH  - Apoptosis/*drug effects
MH  - CTLA-4 Antigen/genetics/*metabolism
MH  - Carcinoma, Non-Small-Cell Lung/genetics/immunology/*metabolism
MH  - Cardenolides/*pharmacology
MH  - Cell Line, Tumor
MH  - Cell Movement/genetics
MH  - Cell Proliferation
MH  - Disease Models, Animal
MH  - Female
MH  - Gene Expression
MH  - Humans
MH  - Lung Neoplasms/genetics/immunology/*metabolism
MH  - *MAP Kinase Signaling System
MH  - Mice
MH  - Transforming Growth Factor beta/*metabolism
MH  - Xenograft Model Antitumor Assays
PMC - PMC5983968
EDAT- 2018/04/06 06:00
MHDA- 2018/09/27 06:00
PMCR- 2018/04/05
CRDT- 2018/04/06 06:00
PHST- 2016/11/09 00:00 [received]
PHST- 2018/02/09 00:00 [accepted]
PHST- 2018/04/06 06:00 [pubmed]
PHST- 2018/09/27 06:00 [medline]
PHST- 2018/04/06 06:00 [entrez]
PHST- 2018/04/05 00:00 [pmc-release]
AID - mmr-17-06-7683 [pii]
AID - 10.3892/mmr.2018.8853 [doi]
PST - ppublish
SO  - Mol Med Rep. 2018 Jun;17(6):7683-7691. doi: 10.3892/mmr.2018.8853. Epub 2018 Apr 
      5.