Isosilybin A induces apoptosis in human prostate cancer cells via targeting Akt, NF-κB, and androgen receptor signaling.
Isosilybin A induces apoptosis in human prostate cancer cells via targeting Akt, NF-κB, and androgen receptor signaling.
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DOI：
10.1002/mc.20670
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发表时间：
2010-10
影响因子：
4.6
通讯作者：
Agarwal, Rajesh
中科院分区：
文献类型：
--
作者：
Deep, Gagan;Gangar, Subhash C.;Oberlies, Nicholas H.;Kroll, David J.;Agarwal, Rajesh
前列腺癌（PCA）是美国男性中第二大恶性肿瘤。晚期PCA细胞具有无限的复制潜力以及对凋亡的抗性。因此，针对生存机制和激活凋亡机制PCA细胞使用无毒的植物化学物质建议作为一个有吸引力的战略，对这种致命的恶性肿瘤。在本研究中，我们评估了一种这样的植物剂，即异水飞蓟宾A，对不同PCA细胞中的凋亡机制和细胞存活信号传导的关键成员[Akt，NF- κB和雄激素受体（AR）]的影响。结果显示，异水飞蓟宾A（90-180 μM）处理在三种不同的人PCA细胞系（即22 Rv 1、LAPC 4和LNCaP）中通过激活细胞凋亡的外源性（增加的DR 5和裂解的caspase 8水平）和内源性途径（caspase 9和caspase 3激活）显著诱导细胞凋亡死亡。此外，异水飞蓟宾A处理降低磷酸化Akt（丝氨酸-473）、总Akt和NF-κB组分（p50和p65）的核水平。异水飞蓟宾A处理还降低了22 Rv 1、LAPC 4和LNCaP细胞的AR和PSA水平。使用泛半胱天冬酶抑制剂（Z-VAD. ffetus），我们证实了异水飞蓟宾A介导的AR降低不依赖于半胱天冬酶的激活。时间动力学分析表明，异水飞蓟宾A的主要作用是对AR的影响，因为AR的降低相对于半胱天冬酶激活和凋亡诱导（12小时）要早得多（4小时）。总之，我们的研究结果表明，异水飞蓟宾A通过靶向Akt-NF-κB-AR轴激活PCA细胞中的凋亡机制;因此，表明这种植物化学物质在临床PCA管理中具有很好的作用。
Prostate cancer (PCA) is second most malignancy in American men. Advanced stage PCA cells possess unlimited replication potential as well as resistance to apoptosis. Therefore, targeting survival mechanisms and activating apoptotic machinery in PCA cells using non-toxic phytochemicals is suggested as an attractive strategy against this deadly malignancy. In the present study, we assessed the effect of one such botanical agent, namely isosilybin A, on apoptotic machinery and key members of cell survival signaling [Akt, NF- κB and androgen receptor (AR)] in different PCA cells. Results showed that isosilybin A (90–180 μM) treatment significantly induces apoptotic death by activating both extrinsic (increased level of DR5 and cleaved caspase 8) and intrinsic pathways (caspase 9 and caspase 3 activation) of apoptosis in three different human PCA cell lines namely 22Rv1, LAPC4 and LNCaP. Further, isosilybin A treatment decreased the levels of phospho-Akt (Serine-473), total Akt and the nuclear levels of NF-κB constituents (p50 and p65). Isosilybin A treatment also decreased the AR and PSA level in 22Rv1, LAPC4 and LNCaP cells. Employing pan-caspase inhibitor (Z-VAD.fmk), we confirmed that isosilybin A-mediated decreased AR is independent of caspases activation. Temporal kinetics analysis showed that the primary effect of isosilybin A is on AR, as decrease in AR was evident much earlier (4h) relative to caspase activation and apoptosis induction (12h). Overall, our results demonstrated that isosilybin A activates apoptotic machinery in PCA cells via targeting Akt-NF-κB-AR axis; thereby, indicating a promising role for this phytochemical in the management of clinical PCA.
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影响因子：
82.9
作者：
Chen, CD;Welsbie, DS;Sawyers, CL
通讯作者：
Sawyers, CL
影响因子：
254.7
作者：
Jemal, Ahmedin;Siegel, Rebecca;Thun, Michael J.
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影响因子：
11.2
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Bhuiyan, Mohammad M. R.;Li, Yiwei;Sarkar, Fazlul H.
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Sarkar, Fazlul H.
影响因子：
2.9
作者：
Kroll, David J.;Shaw, Heather S.;Oberlies, Nicholas H.
通讯作者：
Oberlies, Nicholas H.
影响因子：
8.8
作者：
Le Page C;Koumakpayi IH;Alam-Fahmy M;Mes-Masson AM;Saad F
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Saad F