Role of p53 in the anti-proliferative effects of Sirt1 inhibition in prostate cancer cells.
Role of p53 in the anti-proliferative effects of Sirt1 inhibition in prostate cancer cells.
复制标题
DOI：
10.4161/cc.8.10.8408
复制
发表时间：
2009-05-15
期刊：
影响因子：
--
通讯作者：
Ahmad N
中科院分区：
文献类型：
--
作者：
Jung-Hynes B;Ahmad N
前列腺癌（PCa），仅次于皮肤癌，是美国男性最常见的恶性肿瘤。衰老被认为是这种肿瘤的主要风险因素，因为男性患这种疾病的机会随着年龄的增长而显着增加。由于衰老是不可避免的，美国人的寿命更长，现有的治疗方法无法控制这种肿瘤，因此需要新的基于机制的方法。我们最近发现，Sirt 1，一种sirtuin III类组蛋白脱乙酰酶（HDAC），最初与酵母中的衰老和长寿有关，在人前列腺癌细胞和从患者获得的前列腺癌组织中过表达。我们还发现，化学抑制和/或Sirt 1基因敲低导致FoxO 1介导的抑制人前列腺癌细胞的生长和活力。由于p53是Sirt 1去乙酰化的靶点，我们想确定p53参与Sirt 1抑制介导的PCa反应。为了实现我们的目标，我们利用了一对同基因PCa细胞系，即PC 3和PC 3-p53，它们仅在p53状态上不同。我们的数据表明，Sirt 1抑制引起细胞生长，细胞活力和殖民地形成能力的两种细胞系的下降。此外，Sirt 1抑制导致FoxO 1乙酰化和随后的转录激活在两种细胞类型的增加，无论p53的状态。然而，我们的研究的一个有趣的观察是，Sirt 1抑制导致PC 3-p53细胞衰老的增加，而其导致PC 3细胞凋亡的增加。这项研究的结果补充了我们以前的研究，并表明Sirt 1抑制可能有不同的下游靶点，在细胞与活跃的p53与细胞，其中p53是无活性的。
Prostate Cancer (PCa), next only to skin cancer, is the most commonly occurring malignancy in men in the USA. Aging is recognized as a major risk factor for this neoplasm as a man's chance for developing this disease significantly increases with increasing age. Because aging is inevitable, Americans are living longer, and the existing treatments have not been able to manage this neoplasm, novel mechanism-based approaches are needed. We have recently shown that Sirt1, a sirtuin class III histone deacetylases (HDACs) originally linked to aging and longevity in yeast, was overexpressed in human PCa cells and PCa tissues obtained from patients. We also found that chemical inhibition and/or genetic knockdown of Sirt1 caused a FoxO1-mediated inhibition in the growth and viability of human PCa cells. Since p53 is a target for deacetylation by Sirt1, we wanted to determine the involvement of p53 in Sirt1 inhibition mediated responses in PCa. To achieve our objective, we utilized a pair of isogenic PCa cell lines viz. PC3 and PC3-p53, which differ only in p53 status. Our data demonstrated that Sirt1 inhibition caused a decrease in cell growth, cell viability and the colony formation ability of both cell lines. Further, Sirt1 inhibition resulted in an increase in FoxO1 acetylation and subsequent transcriptional activation in both cell types regardless of p53 status. However, an interesting observation of our study was that Sirt1 inhibition resulted in an increase in senescence in PC3-p53 cells whereas its resulted in an increase in apoptosis in PC3 cells. The results of this study compliment our previous study and suggest that Sirt1 inhibition may have different downstream targets in cells with active p53 versus cells where p53 is inactive.
登录
查看更多内容
影响因子：
11.2
作者：
Chu, F;Chou, PM;Rebbaa, A
通讯作者：
Rebbaa, A
DOI：
10.1196/annals.1395.005
发表时间：
2007-01-01
期刊：
BIOGERONTOLOGY: MECHANISMS AND INTERVENTIONS
影响因子：
--
作者：
Fraga, Mario F.;Agrelo, Ruben;Esteller, Manel
通讯作者：
Esteller, Manel
影响因子：
3.5
作者：
Wang, C;Wang, MW;Ikejima, T
通讯作者：
Ikejima, T
影响因子：
4.8
作者：
Darzynkiewicz, Zbigniew;Galkowski, Dariusz;Zhao, Hong
通讯作者：
Zhao, Hong
影响因子：
8
作者：
Ota, H;Tokunaga, E;Kaneki, M
通讯作者：
Kaneki, M