Pin1 Inhibitor Juglone Exerts Anti-Oncogenic Effects on LNCaP and DU145 Cells despite the Patterns of Gene Regulation by Pin1 Differing between These Cell Lines.
Pin1 Inhibitor Juglone Exerts Anti-Oncogenic Effects on LNCaP and DU145 Cells despite the Patterns of Gene Regulation by Pin1 Differing between These Cell Lines.
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DOI：
10.1371/journal.pone.0127467
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Asano T
中科院分区：
文献类型：
--
作者：
Kanaoka R;Kushiyama A;Seno Y;Nakatsu Y;Matsunaga Y;Fukushima T;Tsuchiya Y;Sakoda H;Fujishiro M;Yamamotoya T;Kamata H;Matsubara A;Asano T
前列腺癌最初以雄激素依赖性的方式发展，但在其发展过程中，在晚期阶段转变为雄激素非依赖性。Pin1是肽基脯氨酸顺式/反式异构酶之一，据报道在前列腺癌中过度表达，并被认为有助于加速细胞生长，这可能是导致其雄激素非依赖性生长的主要因素之一。因此，我们使用微阵列分析研究了Pin1如何调节雄激素依赖性和雄激素非依赖性前列腺癌细胞系中的基因表达。此外，还研究了市售的Pin1抑制剂Juglone的作用。用Pin1 siRNA处理LNCaP（雄激素依赖性）和DU145（雄激素非依赖性）两种前列腺癌细胞，并通过芯片分析其对基因表达的影响。采用RT-PCR检测Pin1 siRNA或Pin1抑制剂Juglone诱导的单个基因调控。此外，还考察了核桃酮对LNCaP和DU145移植小鼠生长的影响。芯片分析显示，LNCaP和DU145细胞中Pin1调控的转录因子有显著差异，唯一的例外是Nrf在两种细胞系中都以相同的方式受到Pin1 siRNA的调控。尽管在基因调控上存在显著差异，但Pin1 siRNA和Juglone对LNCaP和DU145细胞系均有较强的抑制作用，在体外抑制细胞增殖，移植到小鼠体内后抑制肿瘤增大。尽管Pin1调控的基因表达在LNCaP（雄激素依赖性）和DU145（雄激素非依赖性）这两种前列腺癌细胞系之间存在差异，但Pin1抑制抑制了这两种细胞系的增殖。这些发现提示Pin1抑制剂作为前列腺癌治疗药物的潜在有效性，无论其雄激素敏感性如何。
Prostate cancer initially develops in an androgen-dependent manner but, during its progression, transitions to being androgen-independent in the advanced stage. Pin1, one of the peptidyl-prolyl cis/trans isomerases, is reportedly overexpressed in prostate cancers and is considered to contribute to accelerated cell growth, which may be one of the major factors contributing to their androgen-independent growth. Thus, we investigated how Pin1 modulates the gene expressions in both androgen-dependent and androgen-independent prostate cancer cell lines using microarray analysis. In addition, the effects of Juglone, a commercially available Pin1 inhibitor were also examined. Two prostate cancer cell-lines, LNCaP (androgen-dependent) and DU145 (androgen-independent), were treated with Pin1 siRNA and its effects on gene expressions were analyzed by microarray. Individual gene regulations induced by Pin1 siRNA or the Pin1 inhibitor Juglone were examined using RT-PCR. In addition, the effects of Juglone on the growth of LNCaP and DU145 transplanted into mice were investigated. Microarray analysis revealed that transcriptional factors regulated by Pin1 differed markedly between LNCaP and DU145 cells, the only exception being that Nrf was regulated in the same way by Pin1 siRNA in both cell lines. Despite this marked difference in gene regulations, Pin1 siRNA and Juglone exert a strong inhibitory effect on both the LNCaP and the DU145 cell line, suppressing in vitro cell proliferation as well as tumor enlargement when transplanted into mice. Despite Pin1-regulated gene expressions differing between these two prostate cancer cell-lines, LNCaP (androgen-dependent) and DU145 (androgen-independent), Pin1 inhibition suppresses proliferation of both cell-lines. These findings suggest the potential effectiveness of Pin1 inhibitors as therapeutic agents for prostate cancers, regardless of their androgen sensitivity.
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