PMID- 31218844
OWN - NLM
STAT- MEDLINE
DCOM- 20200803
LR  - 20210109
IS  - 2045-7634 (Electronic)
IS  - 2045-7634 (Linking)
VI  - 8
IP  - 9
DP  - 2019 Aug
TI  - The immunostimulatory effects and pro-apoptotic activity of rhCNB against Lewis 
      lung cancer is mediated by Toll-like receptor 4.
PG  - 4441-4453
LID - 10.1002/cam4.2158 [doi]
AB  - BACKGROUND: Recombinant human calcineurin B subunit (rhCNB) has been shown to be 
      an immune-stimulatory protein promoting cytokine production and inducing 
      phenotypic maturation of Dendritic cells (DCs). In vivo, it has good antitumor 
      efficacy, and has potential as an antitumor drug. Exogenous rhCNB was found to be 
      internalized into tumor cells via the Toll-like receptor 4 (TLR4) complex, but it 
      was not known whether its immuno-modulatory and antitumor functions involved 
      entry by this same route. METHODS: The production and secretion of the cytokines 
      and chemokines in innate immune cells induced by rhCNB were determined by ELISA, 
      and the expression of CD40, CD80, CD86, and MHCII was analyzed by FACs. 
      Experimental Lewis lung cancer (LLC) model was prepared in C57 BL/6 wild-type 
      (WT) mice, TLR4(-/-) mice or their littermates by the inoculation of LLCs in 
      their right armpit, and then administrated daily intraperitoneal injections 
      (0.2 mL) of normal saline, rhCNB 20 mg/kg, and rhCNB 40 mg/kg, respectively. 
      RESULTS: Recombinant human calcineurin B subunit promoted the production of 
      antitumor cytokines by innate immune cells, and culture supernatants of 
      rhCNB-stimulated immune cells induced apoptosis of LLCs. In addition, rhCNB 
      up-regulated CD40, CD80, CD86, and MHCII expression in macrophages and DCs in 
      TLR4(+) cells but failed to do so in TLR4 deficient cells. rhCNB also induced the 
      formation of CD4(+) and CD8(+) T cells in splenocytes from WT mice, but not from 
      TLR4-deficient littermates. Intraperitoneal administration of WT C57BL/6 mice 
      with rhCNB resulted in a 50% reduction in LLC tumor growth, but failed to inhibit 
      tumor growth in TLR4(-/-) littermates. CONCLUSIONS: The in vivo antitumor and 
      immunomodulatory effects of rhCNB are mediated by the TLR4. This conclusion is 
      important for the further understanding and development of rhCNB as an antitumor 
      drug.
CI  - (c) 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
FAU - Yang, Jinju
AU  - Yang J
AUID- ORCID: 0000-0001-8688-1264
AD  - Department of Biochemistry and Molecular Biology, Gene Engineering and 
      Biotechnology Beijing Key Laboratory, Beijing Normal University, Beijing, P. R. 
      China.
AD  - National Key Laboratory of Biochemical Engineering, Institute of Process 
      Engineering, Chinese Academy of Sciences, Beijing, China.
FAU - Zhang, Hongwei
AU  - Zhang H
AD  - Department of Biochemistry and Molecular Biology, Gene Engineering and 
      Biotechnology Beijing Key Laboratory, Beijing Normal University, Beijing, P. R. 
      China.
FAU - Zhu, Ziwei
AU  - Zhu Z
AD  - Department of Biochemistry and Molecular Biology, Gene Engineering and 
      Biotechnology Beijing Key Laboratory, Beijing Normal University, Beijing, P. R. 
      China.
FAU - Gao, Yadan
AU  - Gao Y
AD  - Department of Biochemistry and Molecular Biology, Gene Engineering and 
      Biotechnology Beijing Key Laboratory, Beijing Normal University, Beijing, P. R. 
      China.
FAU - Xiang, Benqiong
AU  - Xiang B
AD  - Department of Biochemistry and Molecular Biology, Gene Engineering and 
      Biotechnology Beijing Key Laboratory, Beijing Normal University, Beijing, P. R. 
      China.
FAU - Wei, Qun
AU  - Wei Q
AD  - Department of Biochemistry and Molecular Biology, Gene Engineering and 
      Biotechnology Beijing Key Laboratory, Beijing Normal University, Beijing, P. R. 
      China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190620
PL  - United States
TA  - Cancer Med
JT  - Cancer medicine
JID - 101595310
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Chemokines)
RN  - 0 (Cytokines)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Tlr4 protein, mouse)
RN  - 0 (Toll-Like Receptor 4)
RN  - EC 3.1.3.16 (Calcineurin)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/*administration & dosage/pharmacology
MH  - Calcineurin/*administration & dosage/genetics/pharmacology
MH  - Carcinoma, Lewis Lung/*drug therapy/genetics/immunology/pathology
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Cell Survival/drug effects
MH  - Chemokines/metabolism
MH  - Cytokines/metabolism
MH  - Dose-Response Relationship, Drug
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Gene Knockout Techniques
MH  - Humans
MH  - Injections, Intraperitoneal
MH  - Mice
MH  - Recombinant Proteins/administration & dosage/pharmacology
MH  - Toll-Like Receptor 4/*genetics/*metabolism
MH  - Xenograft Model Antitumor Assays
PMC - PMC6675711
OTO - NOTNLM
OT  - Toll-like receptor 4
OT  - antitumor drug
OT  - antitumor immunity
OT  - innate immunity
OT  - rhCNB
COIS- The authors declare no conflict of interests.
EDAT- 2019/06/21 06:00
MHDA- 2020/08/04 06:00
PMCR- 2019/06/20
CRDT- 2019/06/21 06:00
PHST- 2018/12/02 00:00 [received]
PHST- 2019/03/28 00:00 [accepted]
PHST- 2019/06/21 06:00 [pubmed]
PHST- 2020/08/04 06:00 [medline]
PHST- 2019/06/21 06:00 [entrez]
PHST- 2019/06/20 00:00 [pmc-release]
AID - CAM42158 [pii]
AID - 10.1002/cam4.2158 [doi]
PST - ppublish
SO  - Cancer Med. 2019 Aug;8(9):4441-4453. doi: 10.1002/cam4.2158. Epub 2019 Jun 20.