Plasma membrane-associated sialidase (NEU3) regulates progression of prostate cancer to androgen-independent growth through modulation of androgen receptor signaling
Plasma membrane-associated sialidase (NEU3) regulates progression of prostate cancer to androgen-independent growth through modulation of androgen receptor signaling
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DOI：
10.1038/cdd.2011.83
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发表时间：
2012-01-01
影响因子：
12.4
通讯作者：
Miyagi, T.
中科院分区：
文献类型：
--
作者：
Kawamura, S.;Sato, I.;Miyagi, T.
前列腺癌通常变得雄激素非依赖性，并且随着进展对激素治疗有抗性。为了了解潜在的机制，促进雄激素非依赖性前列腺癌的新治疗方法的发展，我们研究了质膜相关唾液酸酶（NEU 3），参与跨膜信号传导的神经节苷脂水解的关键酶。我们已经发现NEU 3在人前列腺癌中与非癌组织相比上调，与Gleason评分相关。在前列腺癌PC-3和LNCaP细胞中用siRNA沉默NEU 3导致分化标志物和细胞凋亡的表达增加，但Bcl-2以及进展相关的转录因子早期生长反应基因（EGR-1）的表达减少。在雄激素敏感的LNCaP细胞中，NEU 3的强制过表达显著诱导EGR-1、雄激素受体（AR）和PSA的表达，无论是否有雄激素，细胞变得对雄激素敏感。NEU 3介导的诱导被PI-3激酶和MAP激酶的抑制剂废除，更具体地说，在雄激素不存在的情况下，通过AKT和ERK 1/2在NEU 3过表达细胞中的磷酸化增加来证实。NEU 3 siRNA的引入导致培养中的雄激素非依赖性PC-3细胞和裸鼠移植瘤的细胞生长减少。这些数据表明，NEU 3通过AR信号调节肿瘤进展，因此可能成为诊断和治疗雄激素非依赖性前列腺癌的潜在工具。Cell Death and Differentiation（2012）19，170-179; doi：10.1038/cdd.2011.83; 2011年6月17日在线发表
Prostate cancers generally become androgen-independent and resistant to hormone therapy with progression. To understand the underlying mechanisms and facilitate the development of novel treatments for androgen-independent prostate cancer, we have investigated plasma membrane-associated sialidase (NEU3), the key enzyme for ganglioside hydrolysis participating in transmembrane signaling. We have discovered NEU3 to be upregulated in human prostate cancer compared with non-cancerous tissue, correlating with the Gleason score. NEU3 silencing with siRNA in prostate cancer PC-3 and LNCaP cells resulted in increased expression of differentiation markers and in cell apoptosis, but decrease in Bcl-2 as well as a progression-related transcription factor, early growth response gene (EGR-1). In androgen-sensitive LNCaP cells, forced overexpression of NEU3 significantly induced expression of EGR-1, androgen receptor (AR) and PSA both with and without androgen, the cells becoming sensitive to androgen. The NEU3-mediated induction was abrogated by inhibitors for PI-3 kinase and MAP kinase and more specifically by their silencing in the absence of androgen, being confirmed by increased phosphorylation of AKT and ERK1/2 in NEU3 overexpressing cells. NEU3 siRNA introduction caused reduction of cell growth of an androgen-independent PC-3 cells in culture and of transplanted tumors in nude mice. These data suggest that NEU3 regulates tumor progression through AR signaling, and thus be a potential tool for diagnosis and therapy of androgen-independent prostate cancer. Cell Death and Differentiation (2012) 19, 170-179; doi:10.1038/cdd.2011.83; published online 17 June 2011