Duan Xiaolu, Kong Zhenzhen, Liu Yang, Zeng Zhiwen, Li Shujue, Wu Wenqi, Ji Weidong, Yang Bicheng, Zhao Zhijian, Zeng Guohua
Department of Urology, Minimally Invasive Surgery Center, the First Affiliated Hospital of Guangzhou Medical University, Guangdong Key Laboratory of Urology, Guangzhou, Guangdong, China.
Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Collaborative Innovation Center for Neurogenetics and Channelopathies, Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
J Cell Physiol. 2015 Oct;230(10):2371-81. doi: 10.1002/jcp.24963.
β-Arrestin2 has been identified to act as a corepressor of androgen receptor (AR) signaling by binding to AR and serving as a scaffold to affect the activity and expression of AR in androgen-dependent prostate cancer cells; however, little is known regarding its role in castration-resistant prostate cancer (CRPC) progression. Here, our data demonstrated that β-arrestin2 contributes to the cell viability and proliferation of CRPC via the downregulation of FOXO1 activity and expression. Mechanistically, in addition to its requirement for FOXO1 phosphorylation induced by IGF-1, β-arrestin2 could inhibit FOXO1 activity in an Akt-independent manner and delay FOXO1 dephosphorylation through the inhibition of PP2A phosphatase activity and the attenuation of the interaction between FOXO1 and PP2A. Furthermore, β-arrestin2 could downregulate FOXO1 expression via ubiquitylation and proteasomal degradation. Together, our results identified a novel role for β-arrestin2 in the modulation of the CRPC progress through FOXO1. Thus, the characterization of β-arrestin2 may represent an alternative therapeutic target for CRPC treatment.
β-抑制蛋白2已被确定为雄激素受体（AR）信号通路的共抑制因子，它通过与AR结合并作为支架来影响雄激素依赖性前列腺癌细胞中AR的活性和表达；然而，关于其在去势抵抗性前列腺癌（CRPC）进展中的作用知之甚少。在此，我们的数据表明，β-抑制蛋白2通过下调FOXO1的活性和表达促进CRPC的细胞活力和增殖。机制上，除了其对IGF-1诱导的FOXO1磷酸化的需求外，β-抑制蛋白2还可以以不依赖Akt的方式抑制FOXO1的活性，并通过抑制PP2A磷酸酶活性和减弱FOXO1与PP2A之间的相互作用来延迟FOXO1的去磷酸化。此外，β-抑制蛋白2可通过泛素化和蛋白酶体降解下调FOXO1的表达。总之，我们的结果确定了β-抑制蛋白2在通过FOXO1调节CRPC进展中的新作用。因此，β-抑制蛋白2的特性可能代表CRPC治疗的另一种治疗靶点。
