Background/Objectives:Epithelioid Hemangioendothelioma (EHE) is an ultra-rare, metastatic vascular sarcoma with limited therapeutic options. The hallmark of EHE is a chromosomal translocation that produces theWWTR1-CAMTA1gene fusion, encoding the aberrant transcriptional regulator TAZ-CAMTA1. Given its central role in the EHE initiation and progression, TAZ-CAMTA1 represents a compelling therapeutic target.Methods and Results:In this study, we identified AMP-activated protein kinase (AMPK) as one of several proteins capable of repressing the TAZ-CAMTA1 transcriptional activity in NIH3T3 and HEK293 cell lines. The pharmacologic activation of AMPK inhibited the proliferation of EHE cell lines without inducing apoptosis; however, in contrast to the NIH3T3 and HEK293 models, AMPK activation in EHE cells unexpectedly increased the TAZ-CAMTA1 expression and activity. Notably, elevated TAZ-CAMTA1 expression was also associated with reduced EHE cell growth, suggesting that the induction of TAZ-CAMTA1 may be one mechanism by which AMPK suppresses EHE growth. Additionally, we found that AMPK inhibits mTOR activity and that direct mTOR inhibition also suppresses EHE cell growth.Conclusions: Together, these findings demonstrate that AMPK activation impairs EHE viability through dual mechanisms: by promoting TAZ-CAMTA1 expression and by inhibiting mTOR signaling. This work highlights AMPK as a potential therapeutic target in EHE and supports the growing body of evidence favoring mTOR inhibitors as promising treatments for this rare cancer.
背景/目的：上皮样血管内皮瘤是一种超罕见、具有转移性的血管肉瘤，治疗选择有限。该病的特征性染色体易位产生WWTR1-CAMTA1基因融合，编码异常转录调节因子TAZ-CAMTA1。鉴于其在EHE发生发展中的核心作用，TAZ-CAMTA1成为极具潜力的治疗靶点。 方法与结果：本研究通过NIH3T3和HEK293细胞系实验，发现AMP激活蛋白激酶是能够抑制TAZ-CAMTA1转录活性的多个蛋白之一。药物激活AMPK可抑制EHE细胞系增殖而不诱导凋亡；然而与NIH3T3和HEK293模型不同，AMPK在EHE细胞中的激活意外增加了TAZ-CAMTA1的表达和活性。值得注意的是，TAZ-CAMTA1表达升高与EHE细胞生长减缓相关，表明TAZ-CAMTA1诱导可能是AMPK抑制EHE生长的机制之一。此外，我们发现AMPK可抑制mTOR活性，直接抑制mTOR同样能阻碍EHE细胞生长。 结论：综合结果表明，AMPK激活通过双重机制损害EHE细胞活性：促进TAZ-CAMTA1表达与抑制mTOR信号通路。本研究确立了AMPK作为EHE潜在治疗靶点的重要性，并为日益增多的证据支持mTOR抑制剂作为该罕见癌症的有效治疗方案提供了新依据。
AMPK Signaling Regulates Epithelioid Hemangioendothelioma Cell Growth
肿瘤(癌症)患者之家