PMID- 18593367
OWN - NLM
STAT- MEDLINE
DCOM- 20080821
LR  - 20211020
IS  - 1557-8852 (Electronic)
IS  - 1084-9785 (Print)
IS  - 1084-9785 (Linking)
VI  - 23
IP  - 3
DP  - 2008 Jun
TI  - CD4+T cells in CIKs (CD4+ CIKs) reversed resistance to fas-mediated apoptosis 
      through CD40/CD40L ligation rather than IFN-gamma stimulation.
PG  - 342-54
LID - 10.1089/cbr.2007.0454 [doi]
AB  - BACKGROUND: Cytokine-induced killer cells (CIKs) are nonspecific antitumor 
      effectors with superior advantages. CD4+ CIKs can induce Fas-dependent apoptosis 
      in sensitive Raji cells. Here, a Fas-dependent apoptosis was detected in 
      resistant breast cancer MDA-MB-231 cells, and underlying mechanisms were 
      discriminated. METHODS: Amplification of CIKs and purification of CD4+ CIKs were 
      performed in 15 patients with malignant solid tumors. The expression of CD40L and 
      soluble cytokines in CD4+ CIKs were analyzed. The apoptotic rates of tumor cells 
      and the expression of Fas on membranes were detected using flow cytometry assay. 
      The specific blocking antibodies against FasL, CD40L, and interferon-gamma 
      (IFN-gamma) were added to abolish their effects. The changes of 4 
      apoptosis-related genes (Bcl-2, Bax, Fas-associating protein with death domain 
      [FADD], and FLICE inhibitory protein [c-FLIP]) in MDA-MB-231 cells cocultured 
      with CD4+ CIKs were measured by real-time quantitative reverse-transcriptase 
      polymerase chain reaction after 6 hours and 24 hours with or without blocking 
      antibodies. RESULTS: Upregulated expression of membrane-attached CD40L and 
      dramatically increased secretion of soluble CD40L and IFN-gamma were identified 
      in CD4+ CIK. The susceptibility to Fas-mediated apoptosis of insensitive 
      MDA-MB-231 cells was elevated after being pretreated with supernatants from CD4+ 
      CIK. After coculture with CD4+ CIK, apoptosis in MDA-MB-231 cells paralleled with 
      enhanced expression of Fas was blocked fully by either anti-FasL or anti-CD40L, 
      but only partly by anti-IFN-gamma antibodies. The anti-CD40L monoclonal antibody 
      (McAb) rather than anti-IFN-gamma McAb induced significant increase of c-FLIP, 
      which negatively correlated with the apoptosis observed in MDA-MB-231 cells. 
      CONCLUSIONS: Apoptosis in MDA-MB-231 cells induced by CD4+ CIK is Fas-dependent. 
      The reversion of Fas resistance is mediated through CD40/CD40L ligation rather 
      than IFN-gamma stimulation by inhibiting synthesis of c-FLIP.
FAU - Yu, Jinpu
AU  - Yu J
AD  - Department of Immunology, Tianjin Cancer Institute & Hospital of Tianjin Medical 
      University, Tianjin, China.
FAU - Zhang, Weihong
AU  - Zhang W
FAU - Jiang, Huawei
AU  - Jiang H
FAU - Li, Hui
AU  - Li H
FAU - Cao, Shui
AU  - Cao S
FAU - Ren, Xinbao
AU  - Ren X
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Cancer Biother Radiopharm
JT  - Cancer biotherapy & radiopharmaceuticals
JID - 9605408
RN  - 0 (CASP8 and FADD-Like Apoptosis Regulating Protein)
RN  - 0 (CFLAR protein, human)
RN  - 0 (fas Receptor)
RN  - 147205-72-9 (CD40 Ligand)
RN  - 82115-62-6 (Interferon-gamma)
SB  - IM
MH  - Aged
MH  - *Apoptosis
MH  - Breast Neoplasms/metabolism
MH  - CASP8 and FADD-Like Apoptosis Regulating Protein/metabolism
MH  - CD4-Positive T-Lymphocytes/*cytology
MH  - CD40 Ligand/*metabolism
MH  - Cell Line, Tumor
MH  - *Drug Resistance
MH  - Female
MH  - Humans
MH  - Interferon-gamma/*metabolism
MH  - Male
MH  - Middle Aged
MH  - Protein Structure, Tertiary
MH  - fas Receptor/*metabolism
PMC - PMC2936940
EDAT- 2008/07/03 09:00
MHDA- 2008/08/22 09:00
PMCR- 2009/06/01
CRDT- 2008/07/03 09:00
PHST- 2008/07/03 09:00 [pubmed]
PHST- 2008/08/22 09:00 [medline]
PHST- 2008/07/03 09:00 [entrez]
PHST- 2009/06/01 00:00 [pmc-release]
AID - 10.1089/cbr.2007.0454 [pii]
AID - 10.1089/cbr.2007.0454 [doi]
PST - ppublish
SO  - Cancer Biother Radiopharm. 2008 Jun;23(3):342-54. doi: 10.1089/cbr.2007.0454.