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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Oxysterols stimulate Sonic hedgehog signal transduction and proliferation of medulloblastoma cells
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Oxysterols stimulate Sonic hedgehog signal transduction and proliferation of medulloblastoma cells

机译：氧固醇刺激声波刺猬信号转导和髓母细胞瘤细胞增殖

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摘要

Sterol synthesis is required for Sonic hedgehog (Shh) signal transduction. Errors in Shh signal transduction play important roles in the formation of human tumors, including medulloblastoma (MB). It is not clear which products of sterol synthesis are necessary for Shh signal transduction or how they act. Here we show that cholesterol or specific oxysterols are the critical products of sterol synthesis required for Shh pathway signal transduction in MB cells. In MB cells, sterol synthesis inhibitors reduce Shh target gene transcription and block Shh pathway-dependent proliferation. These effects of sterol synthesis inhibitors can be reversed by exogenous cholesterol or specific oxysterols. We also show that certain oxysterols can maximally activate Shh target gene transcription through the Smoothened (Smo) protein as effectively as the known Smo full agonist, SAG. Thus, sterols are required and sufficient for Shh pathway activation. These results suggest that oxysterols may be critical regulators of Smo, and thereby Shh signal transduction. Inhibition of Shh signaling by sterol synthesis inhibitors may offer a novel approach to the treatment of MB and other Shh pathway-dependent human tumors.
机译：声波刺猬（Shh）信号转导需要甾醇合成。 Shh信号转导中的错误在包括髓母细胞瘤（MB）在内的人类肿瘤的形成中起着重要作用。尚不清楚哪种甾醇合成产物对于Shh信号转导是必需的还是如何起作用。在这里，我们表明胆固醇或特定的氧固醇是MB细胞Shh途径信号转导所需的固醇合成的关键产物。在MB细胞中，固醇合成抑制剂可减少Shh靶基因的转录并阻断Shh途径依赖性增殖。固醇合成抑制剂的这些作用可以被外源胆固醇或特定的氧固醇逆转。我们还表明，某些氧固醇可以像已知的Smo完全激动剂SAG一样，最大程度地激活通过Smooth化（Smo）蛋白的Shh目标基因转录。因此，固醇是必需的并且对于Shh途径活化是足够的。这些结果表明，氧固醇可能是Smo的关键调节剂，因此是Shh信号转导的关键。固醇合成抑制剂对Shh信号的抑制可能为MB和其他Shh途径依赖性人类肿瘤的治疗提供一种新颖的方法。

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