The circadian clock gene BMAL1 is a novel therapeutic target for malignant pleural mesothelioma.
The circadian clock gene BMAL1 is a novel therapeutic target for malignant pleural mesothelioma.
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DOI：
10.1002/ijc.27598
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发表时间：
2012-12-15
影响因子：
6.4
通讯作者：
Hasegawa, Yoshinori
中科院分区：
文献类型：
--
作者：
Elshazley, Momen;Sato, Mitsuo;Hase, Tetsunari;Yamashita, Ryo;Yoshida, Kenya;Toyokuni, Shinya;Ishiguro, Futoshi;Osada, Hirotaka;Sekido, Yoshitaka;Yokoi, Kohei;Usami, Noriyasu;Shames, David S.;Kondo, Masashi;Gazdar, Adi F.;Minna, John D.;Hasegawa, Yoshinori
恶性胸膜间皮瘤是一种高度侵袭性的肿瘤，起源于壁层胸膜的间皮细胞，预后差。尽管MPM治疗已经取得了重大进展，但仍需要开发更有效的治疗方法。BMAL 1是生物钟机制的核心组成部分，已报道其在MPM中的组成性过表达。在这里，我们证明BMAL 1可以作为MPM的分子靶点。大多数MPM细胞系和MPM临床标本的一个子集表达的BMAL 1水平分别高于非致瘤性间皮细胞系（MeT-5A）和正常壁胸膜标本。血清休克诱导的节奏性BMAL 1表达的变化，在MeT-5A，但不是在ACC-MESO-1，表明昼夜节律途径是失调的MPM细胞。BMAL 1敲低抑制两种MPM细胞系（ACC-MESO-1和H290）的增殖和锚定依赖性和独立的克隆生长，但在MeT-5A中没有。值得注意的是，BMAL 1耗竭导致细胞周期破坏，凋亡和多倍体细胞群体显著增加，这与Wee 1、细胞周期蛋白B和p21 WAF 1/CIP 1的下调以及细胞周期蛋白E表达的上调有关。BMAL 1敲低诱导有丝分裂灾难，如细胞周期调节因子的破坏和诱导剧烈的形态学变化所示，包括表达最高水平BMAL 1的ACC-MESO-1细胞中的微核和多核。总之，这些发现表明BMAL 1在MPM中具有关键作用，并且可以作为MPM的有吸引力的治疗靶点。
Malignant pleural mesothelioma (MPM) is a highly aggressive neoplasm arising from the mesothelial cells lining the parietal pleura and it exhibits poor prognosis. Although there has been significant progress in MPM treatment, development of more efficient therapeutic approaches is needed. BMAL1 is a core component of the circadian clock machinery and its constitutive overexpression in MPM has been reported. Here, we demonstrate that BMAL1 may serve as a molecular target for MPM. The majority of MPM cell lines and a subset of MPM clinical specimens expressed higher levels of BMAL1 compared to a nontumorigenic mesothelial cell line (MeT-5A) and normal parietal pleural specimens, respectively. A serum shock induced a rhythmical BMAL1 expression change in MeT-5A but not in ACC-MESO-1, suggesting that the circadian rhythm pathway is deregulated in MPM cells. BMAL1 knockdown suppressed proliferation and anchorage-dependent and independent clonal growth in two MPM cell lines (ACC-MESO-1 and H290) but not in MeT-5A. Notably, BMAL1 depletion resulted in cell cycle disruption with a substantial increase in apoptotic and polyploidy cell population in association with downregulation of Wee1, cyclin B and p21WAF1/CIP1 and upregulation of cyclin E expression. BMAL1 knockdown induced mitotic catastrophe as denoted by disruption of cell cycle regulators and induction of drastic morphological changes including micronucleation and multiple nuclei in ACC-MESO-1 cells that expressed the highest level of BMAL1. Taken together, these findings indicate that BMAL1 has a critical role in MPM and could serve as an attractive therapeutic target for MPM.
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