Disruption of a Nuclear NFATc2 Protein Stabilization Loop Confers Breast and Pancreatic Cancer Growth Suppression by Zoledronic Acid
Disruption of a Nuclear NFATc2 Protein Stabilization Loop Confers Breast and Pancreatic Cancer Growth Suppression by Zoledronic Acid
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DOI：
10.1074/jbc.m110.197533
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发表时间：
2011-08-19
影响因子：
4.8
通讯作者：
Ellenrieder, Volker
中科院分区：
文献类型：
--
作者：
Singh, Shiv K.;Baumgart, Sandra;Ellenrieder, Volker
氨基二膦酸盐唑来膦酸由于其显著的抗肿瘤活性而引起了极大的关注，尽管其详细的作用机制仍不清楚。在这里，我们证明了核GSK-3 β-NFATc 2稳定途径的存在，促进乳腺癌和胰腺癌的生长在体外和体内，并作为一个真正的目标唑来膦酸。具体而言，丝氨酸/苏氨酸激酶GSK-3 β通过富含丝氨酸的SP2结构域的磷酸化稳定核NFATc 2，从而保护转录因子免受E3-泛素连接酶HDM 2介导的蛋白水解。唑来膦酸通过两种机制，即GSK-3 β抑制和HDM 2活性诱导，破坏NFATc 2稳定途径。在核积累后，HDM 2靶向未磷酸化的NFATc 2，用于受体赖氨酸残基Lys-684/Lys-897处的泛素化，因此标记该因子用于随后的蛋白酶体降解。相反，诱变诱导的SP2结构域的组成性丝氨酸磷酸化（Ser-215、Ser-219和Ser-223）防止NFATc 2免于HDM 2介导的泛素化和降解，从而拯救癌细胞免于唑来膦酸的生长抑制。总之，这项研究证明了GSK-3 β-HDM 2信号环在调节NFATc 2蛋白稳定性和促进生长方面的关键作用，并表明该途径的双重靶向至少在很大程度上是唑来膦酸有效和可靠的抗肿瘤作用的原因。
The aminobisphosphonate zoledronic acid has elicited significant attention due to its remarkable anti-tumoral activity, although its detailed mechanism of action remains unclear. Here, we demonstrate the existence of a nuclear GSK-3 beta-NFATc2 stabilization pathway that promotes breast and pancreatic cancer growth in vitro and in vivo and serves as a bona fide target of zoledronic acid. Specifically, the serine/threonine kinase GSK-3 beta stabilizes nuclear NFATc2 through phosphorylation of the serine-rich SP2 domain, thus protecting the transcription factor from E3-ubiquitin ligase HDM2-mediated proteolysis. Zoledronic acid disrupts this NFATc2 stabilization pathway through two mechanisms, namely GSK-3 beta inhibition and induction of HDM2 activity. Upon nuclear accumulation, HDM2 targets unphosphorylated NFATc2 for ubiquitination at acceptor lysine residues Lys-684/Lys-897 and hence labels the factor for subsequent proteasomal degradation. Conversely, mutagenesis-induced constitutive serine phosphorylation (Ser-215, Ser-219, and Ser-223) of the SP2 domain prevents NFATc2 from HDM2-mediated ubiquitination and degradation and consequently rescues cancer cells from growth suppression by zoledronic acid. In conclusion, this study demonstrates a critical role of the GSK-3 beta-HDM2 signaling loop in the regulation of NFATc2 protein stability and growth promotion and suggests that double targeting of this pathway is responsible, at least to a significant part, for the potent and reliable anti-tumoral effects of zoledronic acid.