NF-κB 参与了 ShetA2 规避 TNF-α 耐药，但不诱导内在细胞凋亡。
NF-kappaB is involved in SHetA2 circumvention of TNF-alpha resistance, but not induction of intrinsic apoptosis.
机构信息
Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.
出版信息
Anticancer Drugs. 2010 Mar;21(3):297-305. doi: 10.1097/CAD.0b013e3283350e43.
Abstract
Treatment of cancer with tumor necrosis factor-alpha (TNF-alpha) is hindered by resistance and toxicity. The flexible heteroarotinoid, SHetA2, sensitizes resistant ovarian cancer cells to TNF-alpha-induced extrinsic apoptosis, and also induces intrinsic apoptosis as a single agent. This study tested the hypothesis that nuclear factor-kappaB (NF-kappaB) is involved in SHetA2-regulated intrinsic and extrinsic apoptosis. SHetA2 inhibited basal and TNF-alpha-induced or hydrogen peroxide-induced NF-kappaB activity through counter-regulation of upstream kinase (IkappaB kinase) activity, inhibitor protein (IkappaB-alpha) phosphorylation, and p-65 NF-kappaB subunit nuclear translocation, but independently of reactive oxygen species generation. Ectopic over-expression of p-65, or treatment with TNF-alpha receptor 1 (TNFR1) small interfering RNA or a caspase-8 inhibitor, each attenuated synergistic apoptosis by SHetA2 and TNF-alpha, but did not affect intrinsic apoptosis caused by SHetA2. In conclusion, NF-kappaB repression is involved in SHetA2 circumvention of resistance to TNF-alpha-induced extrinsic apoptosis, but not in SHetA2 induction of intrinsic apoptosis.
摘要
用肿瘤坏死因子-α（TNF-α）治疗癌症受到耐药性和毒性的阻碍。灵活的杂芳基硫代乙酰亚胺（SHetA2）使耐药性卵巢癌细胞对 TNF-α诱导的外在细胞凋亡敏感，并且作为单一药物也诱导内在细胞凋亡。本研究检验了核因子-κB（NF-κB）参与 SHetA2 调节的内在和外在细胞凋亡的假设。SHetA2 通过反调节上游激酶（IkappaB 激酶）活性、抑制蛋白（IkappaB-α）磷酸化和 p-65 NF-κB 亚基核易位，抑制基础和 TNF-α诱导或过氧化氢诱导的 NF-κB 活性，但不依赖于活性氧的产生。过表达 p-65，或用 TNF-α受体 1（TNFR1）小干扰 RNA 或半胱天冬酶-8 抑制剂处理，均减弱了 SHetA2 和 TNF-α的协同凋亡，但不影响 SHetA2 引起的内在细胞凋亡。总之，NF-κB 抑制参与了 SHetA2 规避 TNF-α诱导的外在细胞凋亡的耐药性，但不参与 SHetA2 诱导的内在细胞凋亡。
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