Sensitization of SiHa cell to gemcitabine by CD40 activation and its overexpression in cervical carcinoma.
CD40, a member of the tumor necrosis factor receptor superfamily, is widely expressed on various cell types. Some studies show that CD40 expression is related to several carcinomas, where its function remains largely unknown. This study investigated the expression of CD40 on cervical carcinoma and evaluated the effect of agnostic anti-CD40 mAb (5C11) on tumor cell line (SiHa). CD40 expression on the primary cervical carcinoma samples was detected by immunohistochemistry. Results showed that CD40 is commonly expressed in human cervical carcinoma, which is higher than that of normal cervix, cervical precancerous tissue and chronic cervicitis. Treatment of the SiHa cell with the agonistic anti-CD40 monoclonal antibody or Gemcitabine alone did not inhibit the proliferation of the SiHa cell in vitro, but the activation of CD40 on SiHa could enhance its sensitivity to Gemcitabine. Furthermore, CD40 activation blocked SiHa in the S phase, stimulated proapoptotic Bax and inhibited antiapoptotic Bcl-XL mRNA synthesis in the SiHa cell. Apoptosis in SiHa was associated with an increasing ratio of Bax to Bcl-XL in mRNA levels. It is concluded that use of the anti-CD40 mAb 5C11 in combination with chemotherapy may have significant therapeutic potential.
Huang
Qin
Q
Clinical Immunology Laboratory, The First Affiliated Hospital of Soochow University, 188# Shizi Street, 215006, Suzhou, China.
Qu
Qiu-Xia
QX
Xie
Fang
F
Hu
Jian-Ming
JM
Chen
You-Guo
YG
Zhang
Xue-Guang
XG
D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D019013:CD40 Antigens / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002469:Cell Separation; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D002583:Uterine Cervical Neoplasms / Q000378:metabolism*; D000093542:Gemcitabine
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D019013:CD40 Antigens; D003841:Deoxycytidine; D000093542:Gemcitabine
Science. 2001 Apr 27;292(5517):727-30
11326099
Annu Rev Immunol. 2004;22:307-28
15032580
Gynecol Oncol. 2007 Mar;104(3):707-13
17166566
Proc Natl Acad Sci U S A. 2003 Jun 24;100(13):7836-40
12805559
Cell Mol Immunol. 2008 Feb;5(1):33-9
18318992
Hybridoma (Larchmt). 2009 Apr;28(2):121-8
19382845
Proc Natl Acad Sci U S A. 2008 Nov 25;105(47):18081-7
18981409
PLoS Biol. 2008 Jun 10;6(6):e147
18547146
J Immunother. 2009 Jan;32(1):29-35
19307991
Hybridoma. 1999 Dec;18(6):471-8
10626675
J Biol Chem. 2007 Jun 15;282(24):17475-85
17446175
Oncogene. 2003 Nov 20;22(52):8441-7
14627985
Hum Pathol. 2002 Sep;33(9):899-904
12378514
Clin Cancer Res. 2007 Feb 15;13(4):1083-8
17317815
Microbes Infect. 2009 Mar;11(3):429-33
19397878
Cancer Cell. 2006 Nov;10(5):375-88
17097560
Apoptosis. 2005 Jan;10(1):123-34
15711928
Adv Anat Pathol. 2001 Mar;8(2):83-92
11236957
Proc Natl Acad Sci U S A. 2005 Dec 13;102(50):17975-80
16330765