Department of Pediatrics and Neurosurgery, Howard Hughes Medical Institute and Institute for Regeneration Medicine, University of California, San Francisco, San Francisco, California 94143, USA.
Cancer Res. 2010 Jul 1;70(13):5220-5. doi: 10.1158/0008-5472.CAN-10-0554. Epub 2010 Jun 8.
Mouse studies indicate that the synthetic glucocorticoid dexamethasone (Dex) impairs the proliferation of granule neuron precursors in the cerebellum, which are transformed to medulloblastoma by activation of Sonic hedgehog (Shh) signaling. Here, we show that Dex treatment also inhibits Shh-induced tumor growth, enhancing the survival of tumor-prone transgenic mice. We found that Nmyc was specifically required in granule cells for Shh-induced tumorigenesis and that Dex acted to reduce Nmyc protein levels. Moreover, we found that Dex-induced destabilization of Nmyc is mediated by activation of glycogen synthase kinase 3beta, which targets Nmyc for proteasomal degradation. Together, our findings show that Dex antagonizes Shh signaling downstream of Smoothened in medulloblastoma.
小鼠研究表明，合成糖皮质激素地塞米松（Dex）可抑制小脑颗粒神经元前体细胞的增殖，这些细胞在 Sonic hedgehog（Shh）信号的激活下转化为成神经管细胞瘤。在这里，我们表明 Dex 处理还可以抑制 Shh 诱导的肿瘤生长，从而提高易患肿瘤的转基因小鼠的存活率。我们发现 Nmyc 在颗粒细胞中特异性地需要 Shh 诱导的肿瘤发生，并且 Dex 作用于降低 Nmyc 蛋白水平。此外，我们发现 Dex 诱导的 Nmyc 不稳定是通过激活糖原合酶激酶 3β介导的，该激酶将 Nmyc 靶向蛋白酶体降解。总之，我们的研究结果表明，Dex 在成神经管细胞瘤中拮抗 Smoothened 下游的 Shh 信号。
