Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.
Anticancer Drugs. 2010 Mar;21(3):297-305. doi: 10.1097/CAD.0b013e3283350e43.
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.
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。
