Phosphorylation-dependent regulation of ALDH1A1 by Aurora kinase A: insights on their synergistic relationship in pancreatic cancer.
Phosphorylation-dependent regulation of ALDH1A1 by Aurora kinase A: insights on their synergistic relationship in pancreatic cancer.
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DOI：
10.1186/s12915-016-0335-5
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发表时间：
2017-02-13
期刊：
影响因子：
5.4
通讯作者：
Shah K
中科院分区：
文献类型：
--
作者：
Wang J;Nikhil K;Viccaro K;Chang L;White J;Shah K
上皮间质转化（EMT）和癌症干细胞（CSC）形成是促进高致死性胰腺癌广泛转移、耐药性和肿瘤复发的关键潜在原因。导致EMT和CSC表型的机制尚未完全了解，这阻碍了能够改善胰腺癌患者治疗结果的有效靶向治疗的发展。我们显示了极光激酶A（AURKA）通过ALDH 1A 1在促进EMT和CSC表型中的核心作用，ALDH 1A 1是使用创新的化学遗传筛选发现的直接底物。AURKA在三个关键残基上磷酸化ALDH 1A 1，这三个残基对其水平、酶活性和四级结构进行多方面的调节。虽然所有三个磷酸化位点都有助于提高其稳定性，但T267磷酸化主要调节ALDH 1A 1活性。AURKA介导的磷酸化作用使四聚体ALDH 1A 1迅速解离成高活性单体物质。ALDH 1A 1还可以防止AURKA降解，从而触发一个正反馈激活回路，驱动癌症中的高度侵袭性表型。磷酸盐抗性ALDH 1A 1完全逆转EMT和CSC表型，因此作为显性阴性，这强调了AURKA-ALDH 1A 1信号传导轴在胰腺癌中的临床意义。虽然ALDH 1A 1的水平和活性增加是CSC的标志，但潜在的分子机制仍不清楚。我们展示了ALDH 1A 1的第一个磷酸化依赖性调节，通过AURKA增加其水平和活性。最近的全球磷酸化蛋白质组学筛选显示，在ALDH 1A 1高度表达和活跃的人类癌症和健康肝组织中，ALDH 1A 1在T267位点的磷酸化增加，表明这种调节在正常和疾病状态下都可能至关重要。这也是第一项证明ALDH 1A 1的寡聚体依赖性活性的研究，这意味着靶向其寡聚化状态可能是抵消其在癌症中的保护功能的有效治疗方法。最后，虽然AURKA抑制提供了降低ALDH 1A 1水平和活性的有效工具，但它们之间的相互循环确保了它们在抑制高度侵袭性胰腺癌及其他癌症的肿瘤发生、化疗耐药性和转移时的同时抑制将具有高度协同作用。本文的在线版本（doi：10.1186/s12915-016-0335-5）包含补充材料，可供授权用户使用。
Epithelial-to-mesenchymal transition (EMT) and cancer stem cell (CSC) formation are key underlying causes that promote extensive metastasis, drug resistance, and tumor recurrence in highly lethal pancreatic cancer. The mechanisms leading to EMT and CSC phenotypes are not fully understood, which has hindered the development of effective targeted therapies capable of improving treatment outcomes in patients with pancreatic cancer. We show a central role of Aurora kinase A (AURKA) in promoting EMT and CSC phenotypes via ALDH1A1, which was discovered as its direct substrate using an innovative chemical genetic screen. AURKA phosphorylates ALDH1A1 at three critical residues which exert a multifaceted regulation over its level, enzymatic activity, and quaternary structure. While all three phosphorylation sites contribute to its increased stability, T267 phosphorylation primarily regulates ALDH1A1 activity. AURKA-mediated phosphorylation rapidly dissociates tetrameric ALDH1A1 into a highly active monomeric species. ALDH1A1 also reciprocates and prevents AURKA degradation, thereby triggering a positive feedback activation loop which drives highly aggressive phenotypes in cancer. Phospho-resistant ALDH1A1 fully reverses EMT and CSC phenotypes, thus serving as dominant negative, which underscores the clinical significance of the AURKA-ALDH1A1 signaling axis in pancreatic cancer. While increased levels and activity of ALDH1A1 are hallmarks of CSCs, the underlying molecular mechanism remains unclear. We show the first phosphorylation-dependent regulation of ALDH1A1, which increases its levels and activity via AURKA. Recent global phospho-proteomic screens have revealed increased phosphorylation of ALDH1A1 at the T267 site in human cancers and healthy liver tissues where ALDH1A1 is highly expressed and active, indicating that this regulation is likely crucial both in normal and diseased states. This is also the first study to demonstrate oligomer-dependent activity of ALDH1A1, signifying that targeting its oligomerization state may be an effective therapeutic approach for counteracting its protective functions in cancer. Finally, while AURKA inhibition provides a potent tool to reduce ALDH1A1 levels and activity, the reciprocal loop between them ensures that their concurrent inhibition will be highly synergistic when inhibiting tumorigenesis, chemoresistance, and metastasis in highly aggressive pancreatic cancer and beyond. The online version of this article (doi:10.1186/s12915-016-0335-5) contains supplementary material, which is available to authorized users.