Wnt/β-catenin signaling and AXIN1 regulate apoptosis triggered by inhibition of the mutant kinase BRAFV600E in human melanoma.
Wnt/β-catenin signaling and AXIN1 regulate apoptosis triggered by inhibition of the mutant kinase BRAFV600E in human melanoma.
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DOI：
10.1126/scisignal.2002274
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发表时间：
2012-01-10
影响因子：
7.3
通讯作者：
Chien AJ
中科院分区：
文献类型：
--
作者：
Biechele TL;Kulikauskas RM;Toroni RA;Lucero OM;Swift RD;James RG;Robin NC;Dawson DW;Moon RT;Chien AJ
由于Wnt/β-连环蛋白信号通路与黑色素瘤发病机制和患者生存有关，我们在黑色素瘤细胞中进行了激酶组siRNA筛选，以扩大我们对调节该通路的激酶的理解，并阐明潜在的治疗方向。我们发现，BRAF信号，这是组成性激活的许多黑色素瘤的BRAFV 600 E突变，负调控Wnt/β-连环蛋白信号在人类黑色素瘤细胞。由于BRAFV 600 E抑制剂在正在进行的临床试验中显示出前景，我们研究了改变Wnt/β-连环蛋白信号传导是否可以增强BRAFV 600 E抑制剂PLX 4720的功效。令人惊讶的是，内源性β-连环蛋白是PLX 4720诱导黑色素瘤细胞凋亡所必需的，而Wnt/β-连环蛋白信号传导的激活与PLX 4720强烈协同，以减少体内肿瘤生长并增加体外凋亡。这种细胞凋亡的协同增强与β-连环蛋白拮抗剂AXIN 1丰度的减少相关。为了支持AXIN 1是介体而不是凋亡标志物的假设，当AXIN 1被siRNA减少时，在用BRAFV 600 E抑制剂处理后对凋亡具有抗性的黑素瘤细胞系变得敏感，并经历凋亡。这些发现指出了Wnt/β-连环蛋白信号传导和AXIN 1在调节BRAFV 600 E抑制剂疗效中的作用，并可能刺激考虑与靶向BRAF治疗联合使用的潜在联合治疗和生物标志物。
As the Wnt/β-catenin signaling pathway is linked to melanoma pathogenesis and to patient survival, we conducted a kinome siRNA screen in melanoma cells to expand our understanding of kinases that regulate this pathway, and to illuminate potential therapeutic directions. We found that BRAF signaling, which is constitutively activated in many melanomas by the BRAFV600E mutation, negatively regulates Wnt/β-catenin signaling in human melanoma cells. As inhibitors of BRAFV600E show promise in ongoing clinical trials we investigated whether altering Wnt/β-catenin signaling might enhance the efficacy of the BRAFV600E inhibitor, PLX4720. Surprisingly, endogenous β-catenin is required for PLX4720 to induce apoptosis in melanoma cells, while activation of Wnt/β-catenin signaling strongly synergizes with PLX4720 to decrease tumor growth in vivo and to increase apoptosis in vitro. This synergistic enhancement of apoptosis correlates with a reduction in the abundance of a β-catenin antagonist, AXIN1. In support of the hypothesis that AXIN1 is a mediator rather than a marker of apoptosis, melanoma cell lines that are resistant to apoptosis after treatment with a BRAFV600E inhibitor become susceptible, and undergo apoptosis, when AXIN1 is reduced by siRNA. These findings point to a role for Wnt/β-catenin signaling and AXIN1 in regulating the efficacy of inhibitors of BRAFV600E, and may stimulate consideration of potential combination therapies and biomarkers for use in conjunction with targeted BRAF therapy.
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DOI：
10.1038/jid.2008.445
发表时间：
2009-07
期刊：
The Journal of investigative dermatology
影响因子：
--
作者：
Chien AJ;Conrad WH;Moon RT
通讯作者：
Moon RT
影响因子：
4.3
作者：
Cartlidge, Robert A.;Thomas, G. R.;McMahon, Martin
通讯作者：
McMahon, Martin
影响因子：
10.3
作者：
Kageshita, T;Hamby, CV;Ono, T
通讯作者：
Ono, T
通过抑制B-RAFV600E诱导的人类黑色素瘤细胞的凋亡涉及BIMS的优先剪接。
影响因子：
9
作者：
通讯作者：
--
影响因子：
64.8
作者：
通讯作者：
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