Genes Chromosomes & Cancer, 2012, 51(10):961-74.

Genistein Induces Growth Arrest and Suppresses Telomerase Activity in Brain Tumor Cells

Aik Kia Khaw, Jacklyn Wei Yan Yong, Guruprasad Kalthur, et al

Department of Physiology, Genome Stability Laboratory, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Republic of Singapore

Genistein, a soy isoflavone, has been reported to exhibit multiple effects, such as inducing cell cycle arrest, triggering apoptosis, inhibiting the activation of NF(K) B and inactivating several signaling cascades in human cancer cells. In vivo studies demonstrating antiangiogenesis and antimetastatic effects of genistein have also been reported. Here, we demonstrate that genistein inhibits the growth of glioblastoma multiforme and medulloblastoma cells with different TP53 mutations and radio-responses by arresting the cells at G2/M phase of the cell cycle. The cell cycle arrest was found to be independent of DNA damage and such an arrest was sustainable for at least 10 days even after drug removal. Annexin V staining revealed absence of apoptotic or necrotic cell populations after genistein treatment. This supports the observation that genistein induces insignificant DNA damage and indicates that the cell cycle arrest triggered does not lead to cell death. Gene and protein expression studies reveal similar changes in the same pathways following treatment in the cell types tested. Genistein was also able to inhibit telomerase activity resulting in telomere shortening. Thus, we demonstrate, for the first time, that genistein induces growth arrest in association with telomerase inhibition in brain tumor cells via the suppression of TR- and TERT mRNA. By elucidating the mechanisms of anticancer effects after genistein treatment in brain tumor cells, there will be a premise for the incorporation of genistein dietary sources to complement radiotherapy in brain tumor patients.

美国《染色体基因与癌症》，2012年10月

在大脑肿瘤细胞中金雀异黄素诱导生长停滞并抑制端粒酶的活性

埃克 起亚 关，杰克琳 魏 燕 勇，古鲁普若萨德 卡奥泽如等

新加坡共和国国立新加坡大学李永龙医学院基因组稳定性实验室生理学系

金雀异黄素，一种大豆异黄酮，被报道具有多重作用，例如在人类肿瘤细胞中诱导细胞周期阻滞、 触发细胞凋亡、 抑制 NF(K) B 的活性并使几个信号通路失活。表明金雀异黄素的抗血管生成和抗癌细胞扩散及转移的作用的体内研究已被报道。这里，我们证明，金雀异黄素通过不同的TP53突变和无线电响应抑制多形性胶质母细胞瘤和髓母细胞瘤细胞的生长并在 G2/M 期阻滞细胞。我们发现细胞周期阻滞独立于 DNA 损伤，并且这种阻滞会持续至少 10 天甚至在药物去除后仍发挥作用。膜联蛋白 V 染色法表明在经过金雀异黄素治疗后不存在细胞凋亡或坏死的细胞群。这一点支持了金雀异黄素诱导不明显的 DNA 损伤的现象并说明触发细胞周期阻滞不会导致细胞死亡。基因和蛋白表达的研究揭示了经过治疗的测试细胞在相同的路径中的类似的变化。金雀异黄素也能够抑制端粒酶活性进而导致端粒缩短。因此，我们第一次证明，在脑肿瘤细胞中金雀异黄素通过抑制TR-和TERT mRNA诱导端粒酶生长阻滞。通过阐明金雀异黄素治疗脑肿瘤细胞的抗癌作用机制，提出将含金雀异黄素的饮食与放射治疗脑肿瘤患者结合在一起的假设。