Arsenic antagonizes the Hedgehog pathway by preventing ciliary accumulation and reducing stability of the Gli2 transcriptional effector
Arsenic antagonizes the Hedgehog pathway by preventing ciliary accumulation and reducing stability of the Gli2 transcriptional effector
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DOI：
10.1073/pnas.1006822107
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发表时间：
2010-07-27
影响因子：
11.1
通讯作者：
Beachy, Philip A.
中科院分区：
文献类型：
--
作者：
Kim, Jynho;Lee, John J.;Beachy, Philip A.
Hedgehog(HH)通路的异常激活与多种组织和器官的癌症有关，而通路拮抗剂在动物模型中对肿瘤生长的抑制作用促使人们努力开发用于人类治疗目的的通路拮抗剂。这些努力主要集中在环胺衍生物或其他模拟环胺作用的化合物上，这些化合物与膜转导成分Smoothened结合并拮抗。相反，我们在这里报道，砷化合物通过靶向Gli转录效应来拮抗HH途径；在短期内，砷阻止HH诱导的Gli2的纤毛积累，Gli2是HH依赖的转录的主要激活剂，随着孵育时间的延长，砷降低了Gli2的稳定水平。在HH途径拮抗中活跃的砷包括临床用于治疗急性早幼粒细胞白血病(APL)的三氧化二砷(ATO)；在我们的研究中，ATO可以在与治疗人类APL相当的血清水平范围内抑制来自Ptch(+/-)p53(-/-)小鼠的HH途径驱动的同种异体髓母细胞瘤的生长。因此，砷可以作为一种与HH途径激活相关的恶性疾病的治疗剂进行快速测试，并可能在对环胺类化合物具有固有耐药性或已获得耐药性的此类疾病中特别有用。
Aberrant Hedgehog (Hh) pathway activation has been implicated in cancers of diverse tissues and organs, and the tumor growth-inhibiting effects of pathway antagonists in animal models have stimulated efforts to develop pathway antagonists for human therapeutic purposes. These efforts have focused largely on cyclopamine derivatives or other compounds that mimic cyclopamine action in binding to and antagonizing Smoothened, a membrane transductory component. We report here that arsenicals, in contrast, antagonize the Hh pathway by targeting Gli transcriptional effectors; in the short term, arsenic blocks Hh-induced ciliary accumulation of Gli2, the primary activator of Hh-dependent transcription, and with prolonged incubation arsenic reduces steady-state levels of Gli2. Arsenicals active in Hh pathway antagonism include arsenic trioxide (ATO), a curative agent in clinical use for acute promyelocytic leukemia (APL); in our studies, ATO inhibited growth of Hh pathway-driven medulloblastoma allografts derived from Ptch(+/-)p53(-/-) mice within a range of serum levels comparable to those achieved in treatment of human APL. Arsenic thus could be tested rapidly as a therapeutic agent in malignant diseases associated with Hh pathway activation and could be particularly useful in such diseases that are inherently resistant or have acquired resistance to cyclopamine mimics.