Tumor necrosis factor-α sensitizes breast cancer cells to natural products with proteasome-inhibitory activity leading to apoptosis.
Tumor necrosis factor-α sensitizes breast cancer cells to natural products with proteasome-inhibitory activity leading to apoptosis.
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DOI：
10.1371/journal.pone.0113783
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Dou QP
中科院分区：
文献类型：
--
作者：
Lu L;Shi W;Deshmukh RR;Long J;Cheng X;Ji W;Zeng G;Chen X;Zhang Y;Dou QP
炎症微环境在肿瘤发生发展过程中起着重要作用。肿瘤坏死因子-α（TNF-α）是一种重要的促炎细胞因子，在此过程中起重要作用。天然药物产品如Withaferin A（WA）和Celastrol（Cel）已经显示出抗癌和抗炎特性，其可以归因于多种机制，包括但不限于由于抑制蛋白酶体活性而引起的细胞凋亡诱导。本研究旨在探讨肿瘤坏死因子-α（TNF-α）联合WA或Cel对MDA-MB-231乳腺癌细胞的体外作用。当TNF-α与WA或Cel联合时，以剂量依赖性方式激活caspase-3和-9并下调XIAP，导致诱导MDA-MB-231乳腺癌细胞凋亡。该组合还引起蛋白酶体靶蛋白IκBα的蓄积，导致核因子-κB（NF-κB）的核转位受到抑制。总之，这些结果表明TNF-α可以使乳腺癌细胞MDA-MB-231对WA和Cel敏感，至少部分是通过抑制NF-κB信号传导的活化，导致XIAP抑制，随后上调caspase-3和-9活性。因此，当与天然蛋白酶体抑制剂WA或Cel组合时，TNF-α的抗癌活性增强。
The inflammatory microenvironment plays an important role in the process of tumor development. Tumor necrosis factor-α (TNF-α), a key pro-inflammatory cytokine, has a significant role in this process. Natural medicinal products such as Withaferin A (WA) and Celastrol (Cel) have shown anti-cancer and anti-inflammatory properties that can be attributed to multiple mechanisms including, but not limited to, apoptosis induction due to the inhibition of proteasomal activities. This study aimed to investigate the effects of TNF-α in combination with WA or Cel in vitro in MDA-MB-231 breast cancer cells. TNF-α, when combined with WA or Cel, activated caspase-3 and -9 and downregulated XIAP in a dose-dependent manner, leading to induction of apoptosis in MDA-MB-231 breast cancer cells. The combination also caused accumulation of the proteasomal target protein IκBα, resulting in inhibition of the nuclear translocation of nuclear factor-κB (NF-κB). Taken together, these results suggest that TNF-α could sensitize breast cancer cells MDA-MB-231 to WA and Cel, at least in part, through inhibiting the activation of NF-κB signaling, leading to XIAP inhibition with subsequent upregulation of caspase-3 and -9 activities. Thus, the anti-cancer activities of TNF-α are enhanced when combined with the natural proteasome inhibitors, WA or Cel.
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