The C-terminal region of Bfl-1 sensitizes non-small cell lung cancer to gemcitabine-induced apoptosis by suppressing NF-κB activity and down-regulating Bfl-1

Min Kyoung Kim, Yoon Kyung Jeon, Jong Kyu Woo, Yun Choi, Dae Han Choi, Yeul Hong Kim, Chul Woo Kim

Research output: Contribution to journalArticle

13 Citations (Scopus)

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-kB 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-kB activation and concomitant up-regulation of Bfl-1 (an NF-kB-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-kB 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-kB activation and the subsequent overexpression of Bfl-1, and that BC, which has both pro-apoptotic and NF-kB inhibitory effects, could be harnessed as a gene therapy to complement gemcitabine chemotherapy in non-small cell lung cancer.

Original languageEnglish
Article number98
JournalMolecular Cancer
Volume10
DOIs
Publication statusPublished - 2011 Aug 16

Keywords

  • Bfl-1
  • Gemcitabine
  • Gene therapy
  • NF-κB
  • Non-small cell lung cancer

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Cancer Research

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