Open AccessKnockdown of c‐FLIP L enhanced AD5‐10 anti‐death receptor 5 monoclonal antibody‐induced apoptosis in human lung cancer cells
Author(s) -
Chen Feng,
Guo Juntang,
Zhang Yaxi,
Zhao Yu,
Zhou Naikang,
Liu Shilian,
Liu Yanxin,
Zheng Dexian
Publication year - 2009
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2009.01119.x
Subject(s) - apoptosis , lung cancer , cancer research , monoclonal antibody , cell culture , flip , microbiology and biotechnology , cytotoxic t cell , a549 cell , cancer cell , antibody , programmed cell death , cell , gene knockdown , biology , cytochrome c , cancer , chemistry , medicine , immunology , pathology , in vitro , biochemistry , genetics
It is reported that the agonistic antibodies against death receptors 4 and 5 (DR4, DR5) are cytotoxic to various cancer cells. In the present study, the sensitivity of five human lung cancer cell lines to previously reported AD5‐10 agonistic antibody against DR5 were investigated. Of these cell lines, A549 and small cell lung cancer showed a moderate sensitivity to AD5‐10 and three other cell lines were resistant. Cell line H460 is resistant to AD5‐10 despite a high level of cell‐surface DR5 expression. We demonstrated that the resistance of H460 cells to AD5‐10 was not related to the expression level of DR5, but the expression and cleavage of c‐FLIP L in the cells. Inhibition of endogenous c‐FLIP L expression by siRNA significantly enhanced AD5‐10‐induced cell death in these lung cancer cells. We further showed that this sensitizing effect was associated with decreased expression of Bcl‐2 family proteins Bid and Bcl‐X L , change of mitochondrial membrane potential, release of cytochrome c from mitochondria, and caspase activation. Therefore, these data provide evidence that c‐FLIP L is involved in the resistance of lung cancer cells to AD5‐10‐induced apoptosis. Moreover, immunohistochemistry on paraffin‐embedded tissue revealed that c‐FLIP L was expressed in 87.9% (29 of 33) of lung carcinoma tissues from the patients, but little in tissues from normal controls. This suggests that inhibition of c‐FLIP L expression might be a potential strategy for lung cancer therapy, especially for those lung cancers resistant to the agonistic antibody against death receptors. ( Cancer Sci 2009; 100: 940–947)