Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, No. 168, Changhai Rd, Yangpu District, Shanghai, 200433, China.
J Mol Med (Berl). 2012 Oct;90(10):1121-32. doi: 10.1007/s00109-012-0885-0. Epub 2012 Mar 16.
Thalidomide is experimentally used to treat various human cancers; however, clinical responses to thalidomide are sporadic. Here we demonstrate that CUL4A plays an oncogenic role in prostate cancer development and prostate cancer cells with higher level of CUL4A are particularly sensitive to thalidomide treatment. We show that CUL4A is frequently overexpressed in human primary prostate cancer and cell lines. Notably, subjects with tumors that highly expressed CUL4A had poor overall survival. CUL4A downregulation inhibited cell proliferation and induced apoptosis in vitro and in vivo, whereas CUL4A overexpression transformed human normal prostate epithelial cells and promoted invasion, which was attenuated by the extracellular signal-regulated kinase (ERK) inhibitor. We further show that the sensitivity to thalidomide is positively correlated with CUL4A expression in a panel of prostate cell lines. Ectopic CUL4A expression greatly enhanced sensitivity to thalidomide, while its downregulation conferred resistance to this drug. Mechanistically, thalidomide decreased CUL4A in a time- and dose-dependent manner, consequently leading to inaction of ERK pathway. Finally, we show that cereblon level is correlated with CUL4A expression and downregulated in thalidomide-resistant prostate cancer cell. Our results offer the first evidence that CUL4A is a potential therapeutic target for prostate cancer and may serve as a biomarker for assessing prognosis of human prostate cancer and response to thalidomide treatment.
沙利度胺被实验性地用于治疗各种人类癌症；然而，临床对沙利度胺的反应是零星的。在这里，我们证明 CUL4A 在前列腺癌发展中发挥致癌作用，并且 CUL4A 水平较高的前列腺癌细胞对沙利度胺治疗特别敏感。我们表明 CUL4A 在人原发性前列腺癌和细胞系中经常过表达。值得注意的是，CUL4A 高表达的肿瘤患者总体生存率较差。CUL4A 的下调抑制了体外和体内的细胞增殖并诱导了细胞凋亡，而 CUL4A 的过表达则转化了人正常前列腺上皮细胞并促进了侵袭，这被细胞外信号调节激酶 (ERK) 抑制剂减弱。我们进一步表明，在一系列前列腺细胞系中，对沙利度胺的敏感性与 CUL4A 的表达呈正相关。异位 CUL4A 表达大大增强了对沙利度胺的敏感性，而其下调则赋予了对该药物的抗性。在机制上，沙利度胺以时间和剂量依赖的方式降低 CUL4A 的水平，从而导致 ERK 通路失活。最后，我们表明 cereblon 水平与 CUL4A 的表达相关，并在沙利度胺耐药的前列腺癌细胞中下调。我们的结果首次提供了证据，表明 CUL4A 是前列腺癌的潜在治疗靶点，并且可能作为评估人类前列腺癌预后和对沙利度胺治疗反应的生物标志物。
