NF-kappaB is involved in SHetA2 circumvention of TNF-alpha resistance, but not induction of intrinsic apoptosis.
NF-kappaB is involved in SHetA2 circumvention of TNF-alpha resistance, but not induction of intrinsic apoptosis.
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DOI：
10.1097/cad.0b013e3283350e43
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发表时间：
2010-03
影响因子：
2.3
通讯作者：
Benbrook DM
中科院分区：
文献类型：
--
作者：
Chengedza S;Benbrook DM
Treatment of cancer with tumor necrosis factor-α (TNFα) is hindered by resistance and toxicity. The Flexible Heteroarotinoid (Flex-Het), SHetA2, sensitizes resistant ovarian cancer cells to TNFα-induced extrinsic apoptosis, and also induces intrinsic apoptosis as a single agent. This study tested the hypothesis that nuclear factor kappa B (NF-κB) is involved in SHetA2-regulated intrinsic and extrinsic apoptosis. SHetA2 inhibited basal and TNFα- or hydrogen peroxide-induced NF-κB activity through counter-regulation of upstream kinase (IKK) activity, inhibitor protein (IκBα) phosphorylation, and p65 NF-κB subunit nuclear translocation, but independently of reactive oxygen species (ROS) generation. Ectopic over-expression of p65, or treatment with TNFα receptor 1 (TNFR1) siRNA or a caspase 8 inhibitor, each attenuated synergistic apoptosis by SHetA2 and TNFα, but did not affect intrinsic apoptosis caused by SHetA2. In conclusion, NF-κB repression is involved in SHetA2 circumvention of resistance to TNFα-induced extrinsic apoptosis, but not in SHetA2 induction of intrinsic apoptosis.
