Fisetin targets YB-1/RSK axis independent of its effect on ERK signaling: insights from in vitro and in vivo melanoma models.
Fisetin targets YB-1/RSK axis independent of its effect on ERK signaling: insights from in vitro and in vivo melanoma models.
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DOI：
10.1038/s41598-018-33879-w
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发表时间：
2018-10-24
影响因子：
4.6
通讯作者：
Syed DN
中科院分区：
文献类型：
--
作者：
Sechi M;Lall RK;Afolabi SO;Singh A;Joshi DC;Chiu SY;Mukhtar H;Syed DN
膳食类黄酮非瑟酮的抗增殖活性已在各种癌症模型中得到验证。鉴于其目标的多样性，建立其精确的行动机制已证明具有一定的挑战性。我们证明，YB-1促进上皮细胞向间质细胞的转化，并且其抑制抑制肿瘤细胞的增殖和侵袭。p90核糖体S6激酶（RSK）是一种重要的ERK效应子，其激活YB-1以驱动黑色素瘤生长。我们发现，非瑟酮处理单层/3-D黑色素瘤培养物导致YB-1去磷酸化和转录水平降低。同时，非瑟酮抑制黑色素瘤细胞中的间充质标志物和基质金属蛋白酶。来自无细胞/基于细胞的系统的数据表明，非瑟酮通过与激酶结合来抑制RSK活性。RSK亚型的亲和力研究评价了RSK 2的相互作用强于RSK 1。监测结合反应的竞争试验显示YB-1和RSK 2不竞争，而是非瑟酮与RSK 2的结合促进其与YB-1的结合。非瑟酮抑制YB-1/RSK信号转导，而不依赖于其对ERK的作用，并降低MDR 1水平。尽管通过ERK的不同调节，但注意到非瑟酮和维罗非尼抑制黑色素瘤生长的疗效相当。我们的研究提供了对非瑟酮干扰黑色素瘤生长的其他调节模式的深入了解，强调了其在疾病进展中的潜在治疗效果。
The anti-proliferative activity of dietary flavonoid fisetin has been validated in various cancer models. Establishing its precise mechanism of action has proved somewhat challenging given the multiplicity of its targets. We demonstrated that YB-1 promotes epithelial-to-mesenchymal transition and its inhibition suppressed tumor cell proliferation and invasion. The p90 ribosomal S6 kinase (RSK), an important ERK effector, activates YB-1 to drive melanoma growth. We found that fisetin treatment of monolayer/3-D melanoma cultures resulted in YB-1 dephosphorylation and reduced transcript levels. In parallel, fisetin suppressed mesenchymal markers and matrix-metalloproteinases in melanoma cells. Data from cell-free/cell-based systems indicated that fisetin inhibited RSK activity through binding to the kinase. Affinity studies for RSK isoforms evaluated stronger interaction for RSK2 than RSK1. Competition assays performed to monitor binding responses revealed that YB-1 and RSK2 do not compete, rather binding of fisetin to RSK2 promotes its binding to YB-1. Fisetin suppressed YB-1/RSK signaling independent of its effect on ERK, and reduced MDR1 levels. Comparable efficacy of fisetin and vemurafenib for inhibiting melanoma growth was noted albeit through divergent modulation of ERK. Our studies provide insight into additional modes of regulation through which fisetin interferes with melanoma growth underscoring its potential therapeutic efficacy in disease progression.
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影响因子：
3.7
作者：
Law, Jennifer H.;Li, Yvonne;Dunn, Sandra E.
通讯作者：
Dunn, Sandra E.
DOI：
10.1007/978-3-642-54490-3_13
发表时间：
2014-01-01
期刊：
SMALL MOLECULES IN ONCOLOGY, 2ND EDITION
影响因子：
--
作者：
Garbe, Claus;Abusaif, Sail;Eigentler, Thomas K.
通讯作者：
Eigentler, Thomas K.
影响因子：
4.7
作者：
Cho, Yong-Yeon;Lee, Mee-Hyun;Dong, Zigang
通讯作者：
Dong, Zigang
影响因子：
6.5
作者：
Mirmohammadsadegh, Alireza;Mota, Rodrigo;Hengge, Ulrich R.
通讯作者：
Hengge, Ulrich R.
影响因子：
--
作者：
Pal HC;Baxter RD;Hunt KM;Agarwal J;Elmets CA;Athar M;Afaq F
通讯作者：
Afaq F