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.
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.
复制标题
DOI：
10.1186/1476-4598-10-98
复制
发表时间：
2011-08-16
期刊：
影响因子：
37.3
通讯作者：
Kim CW
中科院分区：
文献类型：
--
作者：
Kim MK;Jeon YK;Woo JK;Choi Y;Choi DH;Kim YH;Kim CW
吉西他滨用于治疗包括肺癌在内的多种癌症。然而，肿瘤细胞通常通过多种机制逃避吉西他滨诱导的细胞死亡，这些机制包括调节bcl-2家族成员和NF-κB活化。我们先前报道了Bfl-1的C-末端区域与GFP（BC）融合足以诱导293 T细胞的凋亡。在本研究中，我们研究了联合BC基因治疗和吉西他滨化疗在体外和体内使用非小细胞肺癌细胞系和异种移植模型的抗肿瘤效果。细胞系对低剂量吉西他滨（4-40 ng/ml）具有抗性，吉西他滨诱导NF-κB活化和伴随的Bfl-1（一种NF-κ B调节的抗凋亡蛋白）上调。BC可诱导A549和H157细胞凋亡，并激活caspase-3。此外，与BC和低剂量吉西他滨的共同治疗协同和有效地诱导这些细胞中的细胞凋亡。当单独或与低剂量吉西他滨联合给药时，BC抑制NF-κB活性，抑制p65/relA核转位，并下调Bfl-1表达。此外，通过RNA干扰直接抑制Bfl-1使细胞对吉西他滨诱导的细胞死亡敏感，表明Bfl-1重要地调节肺癌细胞对吉西他滨的敏感性。BC和吉西他滨共治疗在裸鼠/A549异种移植模型中也显示出强的抗肿瘤作用。这些结果表明，肺癌细胞通过NF-κB激活和随后的Bfl-1过表达而对吉西他滨产生耐药性，并且具有促凋亡和NF-κB抑制作用的BC可以作为基因疗法来补充非小细胞肺癌中的吉西他滨化疗。
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.
登录
查看更多内容
影响因子：
4.6
作者：
Denlinger, CE;Rundall, BK;Jones, DR
通讯作者：
Jones, DR
影响因子：
6
作者：
Jones, DR;Broad, RM;Mayo, MW
通讯作者：
Mayo, MW
影响因子：
8
作者：
Cheng, QW;Lee, HH;Cheng, GH
通讯作者：
Cheng, GH
影响因子：
9.7
作者：
Kim, JK;Kim, KD;Lee, HG
通讯作者：
Lee, HG
Bcl-2和Bcl-xL反义处理诱导间皮瘤细胞凋亡和化疗增敏
影响因子：
6.4
作者：
Hopkins-Donaldson, S;Cathomas, R;Zangemeister-Wittke, U
通讯作者：
Zangemeister-Wittke, U