Kim, Min-Kyoung; Jeon, Yoon-Kyung; Woo, Jong-Kyu; Choi, Yun; Choi, Dae-Han; Kim, Yeul-Hong; Kim, Chul-Woo
Molecular cancer
2011NA ; 10 ( 16 ) :98.
PMID : 21843371
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Kim, Min-Kyoung -
Jeon, Yoon-Kyung -
Woo, Jong-Kyu -
Choi, Yun -
Choi, Dae-Han -
Kim, Yeul-Hong -
Kim, Chul-Woo -
ABSTRACT
Gemcitabine is used to treat several cancers including lung cancer. However, tumor cells often escape gemcitabine-induced cell death via various mechanisms, which include modulating bcl-2 family members and NF-κB activation. We previously reported that the C-terminal region of Bfl-1 fused with GFP (BC) is sufficient to induce apoptosis in 293T cells. In the present study, we investigated the anti-tumor effect of combined BC gene therapy and gemcitabine chemotherapy in vitro and in vivo using non-small cell lung cancer cell lines and a xenograft model. Cell lines were resistant to low dose gemcitabine (4-40 ng/ml), which induced NF-κB activation and concomitant up-regulation of Bfl-1 (an NF-κB-regulated anti-apoptotic protein). BC induced the apoptosis of A549 and H157 cells with caspase-3 activation. Furthermore, co-treatment with BC and low dose gemcitabine synergistically and efficiently induced mitochondria-mediated apoptosis in these cells. When administered alone or with low dose gemcitabine, BC suppressed NF-κB activity, inhibited the nuclear translocation of p65/relA, and down-regulated Bfl-1 expression. Furthermore, direct suppression of Bfl-1 by RNA interference sensitized cells to gemcitabine-induced cell death, suggesting that Bfl-1 importantly regulates lung cancer cell sensitivity to gemcitabine. BC and gemcitabine co-treatment also showed a strong anti-tumor effect in a nude mouse/A549 xenograft model. These results suggest that lung cancer cells become resistant to gemcitabine via NF-κB activation and the subsequent overexpression of Bfl-1, and that BC, which has both pro-apoptotic and NF-κB inhibitory effects, could be harnessed as a gene therapy to complement gemcitabine chemotherapy in non-small cell lung cancer.
gemcitabine ?NF-? ?Bfl-1 ?gene therapy ?non-small cell lung cancer
MESH
Animals, Antineoplastic Combined Chemotherapy Protocols/pharmacology/therapeutic use, Carcinoma, Non-Small-Cell Lung/drug therapy/genetics/metabolism/*pathology, Cell Line, Tumor, Deoxycytidine/administration & dosage/analogs & derivatives/pharmacology, Down-Regulation/drug effects/genetics, Drug Synergism, Gene Expression Regulation, Neoplastic/drug effects, HEK293 Cells, Humans, Lung Neoplasms/drug therapy/genetics/metabolism/*pathology, Mice, Mice, Nude, NF-kappa B/*metabolism, Protein Structure, Tertiary/genetics/physiology, Proto-Oncogene Proteins c-bcl-2/administration &, Xenograft Model Antitumor Assays
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