1,4-phenylenebis(methylene)selenocyanate, but not selenomethionine, inhibits androgen receptor and Akt signaling in human prostate cancer cells.
1,4-phenylenebis(methylene)selenocyanate, but not selenomethionine, inhibits androgen receptor and Akt signaling in human prostate cancer cells.
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DOI：
10.1158/1940-6207.capr-10-0054
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发表时间：
2010-08
期刊：
影响因子：
--
通讯作者：
Sinha R
中科院分区：
文献类型：
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作者：
Facompre ND;El-Bayoumy K;Sun YW;Pinto JT;Sinha R
对患有高级别前列腺上皮内瘤变的患者缺乏治疗，加上前列腺癌幸存者的复发和激素抵抗问题，仍然是一个主要的公共卫生障碍。前列腺癌发展的长潜伏期提供了在疾病进展的各个阶段用已知机制的药剂进行干预的机会。许多信号级联已被证明在前列腺癌的发生和进展中起重要作用，包括雄激素受体（AR）和PI 3 K/Akt信号通路。这两种途径之间的串扰也被认为有助于进展和激素难治性前列腺疾病。我们的初步研究表明，天然存在的有机硒化合物硒代甲硫氨酸（SM）和合成的1，4-亚苯基双（亚甲基）硒氰酸酯（p-XSC）可以抑制人前列腺癌细胞的活力;然而，与SM相反，p-XSC在生理相关剂量下具有活性。在目前的研究中，我们表明p-XSC，而不是等效剂量的SM，改变了雄激素响应性LNCaP和雄激素非依赖性LNCaP C4-2人前列腺癌细胞中的分子靶点并诱导细胞凋亡。p-XSC有效抑制两种细胞系中的AR表达和转录活性。p-XSC还降低AR的Akt磷酸化以及Akt特异性磷酸化。然而，Akt的抑制并不能完全减弱p-XSC介导的AR活性下调，这表明p-XSC对AR信号传导的抑制并不仅仅通过PI 3 K/Akt存活途径的改变而发生。我们的数据表明，p-XSC抑制前列腺癌中的多种信号传导途径，可能解释了对增殖和凋亡的下游影响。
The lack of treatment for worried-well patients with high-grade prostatic intraepithelial neoplasia combined with issues of recurrence and hormone resistance in prostate cancer survivors remains a major public health obstacle. The long latency of prostate cancer development provides an opportunity to intervene with agents of known mechanisms at various stages of disease progression. A number of signaling cascades have been shown to play important roles in prostate cancer development and progression, including the androgen receptor (AR) and PI3K/Akt signaling pathways. Crosstalk between these two pathways is also thought to contribute to progression and hormone refractory prostate disease. Our initial investigations show that the naturally occurring organoselenium compound selenomethionine (SM) and synthetic 1,4-phenylenebis(methylene)selenocyanate (p-XSC) can inhibit human prostate cancer cell viability; however, in contrast to SM, p-XSC is active at physiologically relevant doses. In the current investigation we show p-XSC, but not an equivalent dose of SM, alters molecular targets and induces apoptosis in androgen responsive LNCaP and androgen independent LNCaP C4-2 human prostate cancer cells. p-XSC effectively inhibits AR expression and transcriptional activity in both cell lines. p-XSC also decreases Akt phosphorylation as well as Akt-specific phosphorylation of the AR. Inhibition of Akt, however, does not fully attenuate p-XSC-mediated down-regulation of AR activity suggesting inhibition of AR signaling by p-XSC does not occur solely through alterations in the PI3K/Akt survival pathway. Our data suggest that p-XSC inhibits multiple signaling pathways in prostate cancer, likely accounting for down-stream effects on proliferation and apoptosis.