Involvement of AMP-activated protein kinase and Death Receptor 5 in TRAIL-Berberine-induced apoptosis of cancer cells.
Involvement of AMP-activated protein kinase and Death Receptor 5 in TRAIL-Berberine-induced apoptosis of cancer cells.
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DOI：
10.1038/s41598-018-23780-x
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发表时间：
2018-04-03
影响因子：
4.6
通讯作者：
Rana B
中科院分区：
文献类型：
--
作者：
Ke R;Vishnoi K;Viswakarma N;Santha S;Das S;Rana A;Rana B
我们前期的研究表明，肿瘤坏死因子相关凋亡诱导配体（TRAIL）和PPARγ配体曲格列酮（TZD）的组合可以诱导各种TRAIL耐药的前列腺和肝细胞癌（HCC）细胞显着凋亡。这些还表明丝氨酸/苏氨酸激酶 AMP 激活蛋白激酶 (AMPK) 是 TRAIL-TZD 诱导的细胞凋亡的介质。为了进一步验证 AMPK 在 TRAIL 致敏中的作用，我们确定了 TRAIL 与天然化合物小檗碱 (BBR) 组合的细胞凋亡潜力，后者是 AMPK 的有效激活剂。这些结果表明，当用 TRAIL-BBR 组合治疗时，细胞活力显着降低并诱导细胞凋亡（半胱天冬酶 3、8、9 的裂解增加）。在过表达 AMPKα 显性阴性 (DN) 或 AMPKα 敲低后的细胞中，这种细胞凋亡减弱，证实了 AMPK 的参与。为了确定所涉及的潜在下游介质，进行了细胞凋亡 RT2 PCR 阵列分析。这些结果表明，BBR 处理后包括 TNFRSF10B（表达 DR5）和 Harakiri 在内的多个基因被诱导，并通过 qPCR 分析进一步验证。此外，敲低 DR5 表达可显着减弱 TRAIL-BBR 诱导的细胞凋亡，表明 DR5 是这种细胞凋亡的介质。我们的研究表明，TRAIL 和 AMPK 激活剂 BBR 的组合可能是改善晚期癌症中涉及 DR5 的 TRAIL 耐药性的有效方法。
Our previous studies indicated that combination of Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and PPARγ ligand Troglitazone (TZD), can induce significant apoptosis in various TRAIL-resistant prostate and hepatocellular carcinoma (HCC) cells. These also suggested serine/threonine kinase AMP-activated protein kinase (AMPK) to be a mediator of TRAIL-TZD-induced apoptosis. To further validate AMPK’s role in TRAIL sensitization, we determined the apoptotic potential of TRAIL in combination with the natural compound Berberine (BBR), the latter being a potent activator of AMPK. These demonstrated a significant reduction of cell viability and induction of apoptosis (increased cleavage of caspase 3, 8, 9) when treated with TRAIL-BBR combination. This apoptosis is attenuated in cells overexpressing AMPKα-dominant negative (DN) or following AMPKα knockdown, confirming involvement of AMPK. To identify potential downstream mediators involved, an apoptosis RT2 PCR array analysis was performed. These showed induction of several genes including TNFRSF10B (expresses DR5) and Harakiri following BBR treatment, which were further validated by qPCR analysis. Furthermore, knocking down DR5 expression significantly attenuated TRAIL-BBR-induced apoptosis, suggesting DR5 to be a mediator of this apoptosis. Our studies indicate that combination of TRAIL and AMPK activator BBR might be an effective means of ameliorating TRAIL-resistance involving DR5 in advanced cancer.
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影响因子：
--
作者：
Hawley SA;Boudeau J;Reid JL;Mustard KJ;Udd L;Mäkelä TP;Alessi DR;Hardie DG
通讯作者：
Hardie DG
影响因子：
8
作者：
Dimberg LY;Anderson CK;Camidge R;Behbakht K;Thorburn A;Ford HL
通讯作者：
Ford HL
影响因子：
11.5
作者：
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通讯作者：
Cheng, Ann-Lii
影响因子：
5.2
作者：
Lee, Sung-Jun;Noh, Hyo-Jeong;Lee, Tae-Jin
通讯作者：
Lee, Tae-Jin
影响因子：
11.2
作者：
Mukhopadhyay, UK;Senderowicz, AM;Ferbeyre, G
通讯作者：
Ferbeyre, G