Aplysin sensitizes cancer cells to TRAIL by suppressing P38 MAPK/survivin pathway.
Aplysin sensitizes cancer cells to TRAIL by suppressing P38 MAPK/survivin pathway.
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Aplysin 通过抑制 P38 MAPK/Survivin 通路使癌细胞对 TRAIL 敏感
DOI：
10.3390/md12095072
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发表时间：
2014-09-25
期刊：
影响因子：
5.4
通讯作者：
Lin X
中科院分区：
文献类型：
--
作者：
Liu J;Ma L;Wu N;Liu G;Zheng L;Lin X
肿瘤坏死因子相关的凋亡诱导配体(TRAIL)是一种肿瘤选择性的细胞凋亡诱导剂，已被证明在治疗各种类型的癌症方面具有很好的应用前景。然而，肿瘤细胞对TRAIL作用的耐药性极大地阻碍了TRAIL的应用。研究表明，一些关键的促生存蛋白的过度表达，如Survivin，与TRAIL耐药有关。在本研究中，我们发现来自海洋生物的溴化化合物Aplysin在体外和体内都能够恢复癌细胞对TRAIL的敏感性。研究发现，Aplysin能增强TRAIL对几种TRAIL耐药癌细胞的抑瘤作用。A549和MCF7细胞经Aplysin处理后，TRAIL诱导的细胞凋亡也得到加强。Survivin下调被认为是Aplysin介导的TRAIL增敏癌细胞的机制。此外，p38MAPK在Aplysin处理的癌细胞中被激活，其抑制剂SB203580能够阻断Aplysin对TRAIL作用的促进作用，表现为恢复Survivin的表达，提高细胞存活率和降低凋亡率。综上所述，我们提供了Aplysin对TRAIL起增敏作用的证据，其对p38MAPK/Survivin通路的影响可能是这种活性的部分原因。考虑到Aplysin对正常细胞的低毒性，Aplysin可能是一种与TRAIL联合治疗癌症的有前途的药物。
TNF-related apoptosis-inducing ligand (TRAIL) is a tumor-selective apoptosis inducer and has been shown to be promising for treating various types of cancers. However, the application of TRAIL is greatly impeded by the resistance of cancer cells to its action. Studies show that overexpression of some critical pro-survival proteins, such as survivin, is responsible for TRAIL resistance. In this study, we found that Aplysin, a brominated compound from marine organisms, was able to restore the sensitivity of cancer cells to TRAIL both in vitro and in vivo. Aplysin was found to enhance the tumor-suppressing capacity of TRAIL on several TRAIL-resistant cancer cell lines. TRAIL-induced apoptosis was also potentiated in A549 and MCF7 cells treated with Aplysin. Survivin downregulation was identified as a mechanism by which Aplysin-mediated TRAIL sensitization of cancer cells. Furthermore, the activation of p38 MAPK was revealed in Aplysin-treated cancer cells, and its inhibitor SB203580 was able to abrogate the promoting effect of Aplysin on the response of cancer cells to TRAIL action, as evidenced by restored survivin expression, elevated cell survival and reduced apoptotic rates. In conclusion, we provided evidence that Aplysin acts as a sensitizer for TRAIL and its effect on p38 MAPK/survivin pathway may partially account for this activity. Considering its low cytotoxicity to normal cells, Aplysin may be a promising agent for cancer treatment in combination with TRAIL.
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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：
56.9
作者：
Pan, GH;ORourke, K;Dixit, VM
通讯作者：
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影响因子：
4.7
作者：
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影响因子：
9.7
作者：
Weng, Danhui;Song, Xiaohong;Ma, Ding
通讯作者：
Ma, Ding
DOI：
10.3324/haematol.2011.046466
发表时间：
2012-01-01
期刊：
HAEMATOLOGICA-THE HEMATOLOGY JOURNAL
影响因子：
--
作者：
Jacquemin, Guillaume;Granci, Virginie;Micheau, Olivier
通讯作者：
Micheau, Olivier