TRAP1 Is Involved in BRAF Regulation and Downstream Attenuation of ERK Phosphorylation and Cell-Cycle Progression: A Novel Target for BRAF-Mutated Colorectal Tumors
TRAP1 Is Involved in BRAF Regulation and Downstream Attenuation of ERK Phosphorylation and Cell-Cycle Progression: A Novel Target for BRAF-Mutated Colorectal Tumors
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DOI：
10.1158/0008-5472.can-14-1331
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发表时间：
2014-11-15
期刊：
影响因子：
11.2
通讯作者：
Landriscina, Matteo
中科院分区：
文献类型：
--
作者：
Condelli, Valentina;Piscazzi, Annamaria;Landriscina, Matteo
人BRAF驱动的肿瘤是侵袭性恶性肿瘤，临床结果较差，对治疗缺乏敏感性。TRAP 1是一种在人类肿瘤中失调的HSP 90分子伴侣，负责癌细胞的特异性特征，即，保护免于细胞凋亡、耐药性、代谢调节和蛋白质质量控制/泛素化。TRAP 1对BRAF通路起调节作用的假设，源于TRAP 1干扰后BRAF水平降低的观察，在体外和体内在人乳腺癌和结肠直肠癌中进行了测试。这项研究表明，TRAP 1参与调节BRAF合成/泛素化，而不影响其稳定性。事实上，BRAF的合成在TRAP 1丰富的背景下是容易的，而增加的泛素化发生在TRAP 1网络的破坏后，这与蛋白质水平的降低有关。值得注意的是，BRAF下游通路受TRAP 1调节活性调节：实际上，TRAP 1沉默诱导（i）ERK磷酸化减弱，（ii）细胞周期抑制，细胞在G（0）-G（1）和G（2）-M转换中积累，以及（iii）基因表达的广泛重编程。有趣的是，TRAP 1敲低细胞的全基因组分析将细胞生长和细胞周期调控确定为TRAP 1网络控制的最重要的生物功能。值得注意的是，TRAP 1对BRAF的调控在人类结直肠癌中是保守的，这两种蛋白质经常共表达。最后，双重HSP 90/TRAP 1抑制剂HSP 990在BRAF突变的结直肠癌细胞中显示出对TRAP 1网络的活性和高细胞抑制潜力。因此，这种新的TRAP 1功能代表了BRAF驱动的肿瘤对TRAP 1翻译/质量控制机制的靶向依赖性的有吸引力的治疗窗口。(C)2014年AACR。
Human BRAF-driven tumors are aggressive malignancies with poor clinical outcome and lack of sensitivity to therapies. TRAP1 is a HSP90 molecular chaperone deregulated in human tumors and responsible for specific features of cancer cells, i.e., protection from apoptosis, drug resistance, metabolic regulation, and protein quality control/ubiquitination. The hypothesis that TRAP1 plays a regulatory function on the BRAF pathway, arising from the observation that BRAF levels are decreased upon TRAP1 interference, was tested in human breast and colorectal carcinoma in vitro and in vivo. This study shows that TRAP1 is involved in the regulation of BRAF synthesis/ubiquitination, without affecting its stability. Indeed, BRAF synthesis is facilitated in a TRAP1-rich background, whereas increased ubiquitination occurs upon disruption of the TRAP1 network that correlates with decreased protein levels. Remarkably, BRAF downstream pathway is modulated by TRAP1 regulatory activity: indeed, TRAP1 silencing induces (i) ERK phosphorylation attenuation, (ii) cell-cycle inhibition with cell accumulation inG(0)-G(1) andG(2)-Mtransitions, and (iii) extensive reprogramming of gene expression. Interestingly, a genome-wide profiling of TRAP1-knockdown cells identified cell growth and cell-cycle regulation as the most significant biofunctions controlled by the TRAP1 network. It is worth noting that TRAP1 regulation on BRAF is conserved in human colorectal carcinomas, with the two proteins being frequently coexpressed. Finally, the dual HSP90/TRAP1 inhibitor HSP990 showed activity against the TRAP1 network and high cytostatic potential in BRAF-mutated colorectal carcinoma cells. Therefore, this novel TRAP1 function represents an attractive therapeutic window to target dependency of BRAF-driven tumors on TRAP1 translational/quality control machinery. (C) 2014 AACR.