Canonical and noncanonical Hedgehog pathway in the pathogenesis of multiple myeloma
Canonical and noncanonical Hedgehog pathway in the pathogenesis of multiple myeloma
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DOI：
10.1182/blood-2011-07-368142
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发表时间：
2012-12-13
期刊：
影响因子：
20.3
通讯作者：
Munshi, Nikhil C.
中科院分区：
文献类型：
--
作者：
Blotta, Simona;Jakubikova, Jana;Munshi, Nikhil C.
Hedgehog（Hh）通路是胚胎生命期间细胞命运决定以及成年生物体中细胞生长和分化所必需的，其中不适当的激活与几种癌症有关。在这里，我们证明了Hh信号在多发性骨髓瘤（MM）细胞的生长和存活中起着重要作用。我们观察到CD 138（+）MM细胞表达Hh基因，并使用新型合成Smo抑制剂NVP-LDE 225（Novartis）证实了MM中的Smoothened（Smo）依赖性Hh信号传导，NVP-LDE 225通过诱导特异性下调Gli 1和Ptch 1（Hh活性的标志）降低MM细胞活力。此外，我们检测到Gli 1在MM细胞的核定位，这是完全废除毛喉素，Gli 1调节化合物，确认Smo独立的机制，导致Hh在MM激活。最后，我们确定了骨髓基质细胞是一个来源的Shh配体，虽然他们是耐Hh抑制剂，因为缺陷Smo表达和Ptch 1上调。进一步的体外和体内研究显示NVP-LDE 225与硼替佐米组合的抗肿瘤功效。总之，我们的数据表明MM中经典和非经典Hh通路的激活，从而为在临床试验中测试Hh抑制剂以改善MM患者结局提供了理论基础。（血。2012; 120（25）：5002-5013）
The Hedgehog (Hh) pathway is required for cell-fate determination during the embryonic life, as well as cell growth and differentiation in the adult organism, where the inappropriate activation has been implicated in several cancers. Here we demonstrate that Hh signaling plays a significant role in growth and survival of multiple myeloma (MM) cells. We observed that CD138(+) MM cells express Hh genes and confirmed Smoothened (Smo)-dependent Hh signaling in MM using a novel synthetic Smo inhibitor, NVP-LDE225 (Novartis), which decreased MM cell viability by inducing specific downregulation of Gli1 and Ptch1, hallmarks of Hh activity. In addition, we detected a nuclear localization of Gli1 in MM cells, which is completely abrogated by Forskolin, a Gli1-modulating compound, confirming Smo-independent mechanisms leading to Hh activation in MM. Finally, we identified that bone marrow stromal cells are a source of the Shh ligand, although they are resistant to the Hh inhibitor because of defective Smo expression and Ptch1 up-regulation. Further in vitro as well as in vivo studies showed antitumor efficacy of NVP-LDE225 in combination with bortezomib. Altogether, our data demonstrate activation of both canonical and noncanonical Hh pathway in MM, thus providing the rationale for testing Hh inhibitors in clinical trials to improve MM patient outcome. (Blood. 2012; 120(25): 5002-5013)