Myb overexpression overrides androgen depletion-induced cell cycle arrest and apoptosis in prostate cancer cells, and confers aggressive malignant traits: potential role in castration resistance
Myb overexpression overrides androgen depletion-induced cell cycle arrest and apoptosis in prostate cancer cells, and confers aggressive malignant traits: potential role in castration resistance
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DOI：
10.1093/carcin/bgs134
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发表时间：
2012-11-01
期刊：
影响因子：
4.7
通讯作者：
Singh, Ajay P.
中科院分区：
文献类型：
--
作者：
Srivastava, Sanjeev K.;Bhardwaj, Arun;Singh, Ajay P.
Myb 是 v-Myb 癌基因的细胞祖细胞，在前列腺癌中扩增，并且在激素难治性疾病中表现出更高的扩增频率。在这里，我们研究了 Myb 在前列腺癌中的功能意义。我们的研究表明 Myb 在所有检查的前列腺癌细胞系（LNCaP、C4-2、PC3 和 DU145）中表达，而在正常/良性前列腺上皮细胞（RWPE1 和 RWPE2）中表达可忽略不计。值得注意的是，与相同基因型谱系的雄激素依赖性 (I,NCaP) 前列腺癌细胞相比，去势抵抗 (C4-2) 细胞中 Myb 在转录物（>60 倍）和蛋白质（>15 倍）水平上均显着上调。使用功能丧失和获得方法，我们证明 Myb 通过诱导细胞周期蛋白（A1、D1 和 E1）、Bcl-xl 和 Bcl2 以及下调 p27 和 Bax，分别在雄激素补充和剥夺条件下促进和维持细胞周期进展和存活。有趣的是，Myb 过度表达也与前列腺特异性抗原表达增强有关。此外，我们的数据显示 Myb 在增强前列腺癌细胞的运动性和侵袭性以及减少同型相互作用方面发挥作用。 Myb 过度表达还与肌动蛋白重组相关，导致丝状伪足样细胞突起的形成。免疫印迹分析表明，在 Myb 过表达的 LNCaP 和沉默的 C4-2 细胞中，间质标记物获得了，上皮标记物丢失了，反之亦然，表明 Myb 在上皮细胞向间质转化中的作用。总而言之，我们的研究为 Myb 在前列腺癌细胞生长和恶性行为中的功能作用提供了第一个实验证据，并提出了一种新的去势抵抗机制。
Myb, a cellular progenitor of v-Myb oncogenes, is amplified in prostate cancer and exhibits greater amplification frequency in hormone-refractory disease. Here, we have investigated the functional significance of Myb in prostate cancer. Our studies demonstrate Myb expression in all prostate cancer cell lines (LNCaP, C4-2, PC3 and DU145) examined, whereas it is negligibly expressed in normal/benign prostate epithelial cells (RWPE1 and RWPE2). Notably, Myb is significantly upregulated, both at transcript (>60-fold) and protein (>15-fold) levels, in castration-resistant (C4-2) cells as compared with androgen-dependent (I,NCaP) prostate cancer cells of the same genotypic lineage. Using loss and gain of function approaches, we demonstrate that Myb promotes and sustains cell cycle progression and survival under androgen-supplemented and -deprived conditions, respectively, through induction of cyclins (A1, D1 and E1), BcI-xl, and BcI2 and downregulation of p27 and Bax. Interestingly, Myb overexpression is also associated with enhanced prostate-specific antigen expression. Furthermore, our data show a role of Myb in enhanced motility and invasion and decreased homotypic interactions of prostate cancer cells. Myb overexpression is also associated with actin reorganization leading to the formation of filopodia-like cellular protrusions. Immunoblot analyses demonstrate gain of mesenchymal and loss of epithelial markers and vice versa, in Myb-overexpressing LNCaP and -silenced C4-2 cells, respectively, indicating a role of Myb in epithelial to mesenchymal transition. Altogether, our studies provide first experimental evidence for a functional role of Myb in growth and malignant behavior of prostate cancer cells and suggest a novel mechanism for castration resistance.