Beck Tim N, Korobeynikov Vladislav A, Kudinov Alexander E, Georgopoulos Rachel, Solanki Nehal R, Andrews-Hoke Magda, Kistner Timothy M, Pépin David, Donahoe Patricia K, Nicolas Emmanuelle, Einarson Margret B, Zhou Yan, Boumber Yanis, Proia David A, Serebriiskii Ilya G, Golemis Erica A
Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Program in Molecular and Cell Biology and Genetics, Drexel University College of Medicine, Philadelphia, PA 19129, USA.
Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Medical Department, Novosibirsk State University, Novosibirsk 630090, Russia.
Cell Rep. 2016 Jul 19;16(3):657-71. doi: 10.1016/j.celrep.2016.06.043. Epub 2016 Jul 7.
Anti-Müllerian hormone (AMH) and its type II receptor AMHR2, both previously thought to primarily function in gonadal tissue, were unexpectedly identified as potent regulators of transforming growth factor (TGF-β)/bone morphogenetic protein (BMP) signaling and epithelial-mesenchymal transition (EMT) in lung cancer. AMH is a TGF-β/BMP superfamily member, and AMHR2 heterodimerizes with type I receptors (ALK2, ALK3) also used by the type II receptor for BMP (BMPR2). AMH signaling regulates expression of BMPR2, ALK2, and ALK3, supports protein kinase B-nuclear factor κB (AKT-NF-κB) and SMAD survival signaling, and influences BMP-dependent signaling in non-small cell lung cancer (NSCLC). AMH and AMHR2 are selectively expressed in epithelial versus mesenchymal cells, and loss of AMH/AMHR2 induces EMT. Independent induction of EMT reduces expression of AMH and AMHR2. Importantly, EMT associated with depletion of AMH or AMHR2 results in chemoresistance but sensitizes cells to the heat shock protein 90 (HSP90) inhibitor ganetespib. Recognition of this AMH/AMHR2 axis helps to further elucidate TGF-β/BMP resistance-associated signaling and suggests new strategies for therapeutic targeting of EMT.
抗苗勒管激素（AMH）及其II型受体AMHR2，此前被认为主要在性腺组织中发挥作用，却意外地被确定为肺癌中转化生长因子（TGF-β）/骨形态发生蛋白（BMP）信号传导和上皮-间质转化（EMT）的有效调节因子。AMH是TGF-β/BMP超家族成员，AMHR2与I型受体（ALK2、ALK3）形成异二聚体，而BMP的II型受体（BMPR2）也使用这些I型受体。AMH信号传导调节BMPR2、ALK2和ALK3的表达，支持蛋白激酶B-核因子κB（AKT-NF-κB）和SMAD存活信号传导，并影响非小细胞肺癌（NSCLC）中BMP依赖的信号传导。AMH和AMHR2在上皮细胞与间充质细胞中选择性表达，AMH/AMHR2的缺失会诱导EMT。EMT的独立诱导会降低AMH和AMHR2的表达。重要的是，与AMH或AMHR2耗竭相关的EMT会导致化疗耐药，但会使细胞对热休克蛋白90（HSP90）抑制剂ganetespib敏感。对这一AMH/AMHR2轴的认识有助于进一步阐明与TGF-β/BMP耐药相关的信号传导，并为EMT的治疗靶向提供新策略。
