Inhibition of the Nrf2 transcription factor by the alkaloid trigonelline renders pancreatic cancer cells more susceptible to apoptosis through decreased proteasomal gene expression and proteasome activity
Inhibition of the Nrf2 transcription factor by the alkaloid trigonelline renders pancreatic cancer cells more susceptible to apoptosis through decreased proteasomal gene expression and proteasome activity
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DOI：
10.1038/onc.2012.493
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发表时间：
2013-10-03
期刊：
影响因子：
8
通讯作者：
Schaefer, H.
中科院分区：
文献类型：
--
作者：
Arlt, A.;Sebens, S.;Schaefer, H.
越来越多的证据表明，转录因子核因子E2相关因子2（Nrf 2）在癌症发展和耐药性中起着重要作用，因此指出其作为抗癌靶点的潜力，并破坏了其在化学预防中的适用性。通过诱导细胞保护基因和蛋白酶体基因，Nrf 2在肿瘤细胞中赋予凋亡保护，因此抑制Nrf 2将是抗癌治疗的有效策略。在本研究中，胰腺癌细胞系（Panc 1，Colo 357和MiaPaca 2）和H6 c7胰管细胞分析了咖啡生物碱胡芦巴碱（Trigonelline）的Nrf 2抑制作用，以及其对Nrf 2依赖性蛋白酶体活性和对肿瘤坏死因子相关凋亡诱导配体（TRAIL）和抗癌药物诱导的细胞凋亡的抵抗的影响。化学抗性Panc 1和Colo 357细胞表现出高的组成性Nrf 2活性，而化学敏感的MiaPaca 2和H6 c7细胞表现出很少的基础，但强的叔丁基氢醌（tBHQ）诱导的Nrf 2活性和耐药性。Trig有效地降低了所有细胞系中的基础和tBHQ诱导的Nrf 2活性，这种作用依赖于Nrf 2蛋白的核积累减少。沿着Nrf 2抑制，在所有测试的细胞系中，顺铂阻断蛋白酶体基因（例如，s5 a/psmd 4和alpha 5/psma 5）的Nrf 2依赖性表达，并降低蛋白酶体活性。在用Nrf 2 siRNA处理后，这些阻断作用不存在，在这种情况下，蛋白酶体基因表达和蛋白酶体活性已经降低，而针对相关转录因子Nrf 1的siRNA不影响蛋白酶体活性和trig的抑制作用。所有细胞系对抗癌药物和TRAIL诱导的凋亡的敏感性都被trigg增强。此外，在接受trigg的荷瘤小鼠中观察到对抗癌药物治疗的更大的抗肿瘤反应。总之，作为能够阻断Nrf 2依赖性蛋白酶体活性并由此保护胰腺癌细胞凋亡的有效Nrf 2抑制剂，顺铂可能有益于改善抗癌治疗。
Evidence accumulates that the transcription factor nuclear factor E2-related factor 2 (Nrf2) has an essential role in cancer development and chemoresistance, thus pointing to its potential as an anticancer target and undermining its suitability in chemoprevention. Through the induction of cytoprotective and proteasomal genes, Nrf2 confers apoptosis protection in tumor cells, and inhibiting Nrf2 would therefore be an efficient strategy in anticancer therapy. In the present study, pancreatic carcinoma cell lines (Panc1, Colo357 and MiaPaca2) and H6c7 pancreatic duct cells were analyzed for the Nrf2-inhibitory effect of the coffee alkaloid trigonelline (trig), as well as for its impact on Nrf2-dependent proteasome activity and resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and anticancer drug-induced apoptosis. Chemoresistant Panc1 and Colo357 cells exhibit high constitutive Nrf2 activity, whereas chemosensitive MiaPaca2 and H6c7 cells display little basal but strong tert-butylhydroquinone (tBHQ)-inducible Nrf2 activity and drug resistance. Trig efficiently decreased basal and tBHQ-induced Nrf2 activity in all cell lines, an effect relying on a reduced nuclear accumulation of the Nrf2 protein. Along with Nrf2 inhibition, trig blocked the Nrf2-dependent expression of proteasomal genes (for example, s5a/psmd4 and alpha 5/psma5) and reduced proteasome activity in all cell lines tested. These blocking effects were absent after treatment with Nrf2 siRNA, a condition in which proteasomal gene expression and proteasome activity were already decreased, whereas siRNA against the related transcription factor Nrf1 did not affect proteasome activity and the inhibitory effect of trig. Depending on both Nrf2 and proteasomal gene expression, the sensitivity of all cell lines to anticancer drugs and TRAIL-induced apoptosis was enhanced by trig. Moreover, greater antitumor responses toward anticancer drug treatment were observed in tumor-bearing mice when receiving trig. In conclusion, representing an efficient Nrf2 inhibitor capable of blocking Nrf2-dependent proteasome activity and thereby apoptosis protection in pancreatic cancer cells, trig might be beneficial in improving anticancer therapy.