Progesterone receptors induce FOXO1-dependent senescence in ovarian cancer cells
Progesterone receptors induce FOXO1-dependent senescence in ovarian cancer cells
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DOI：
10.4161/cc.24550
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发表时间：
2013-05-01
期刊：
影响因子：
4.3
通讯作者：
Lange, Carol A.
中科院分区：
文献类型：
--
作者：
Diep, Caroline H.;Charles, Nathan J.;Lange, Carol A.
核黄体酮受体（PR）的缺失和低循环黄体酮水平与卵巢癌（OC）风险增加有关。然而，PR在浆液性和子宫内膜样卵巢肿瘤中大量表达；PR阳性肿瘤患者通常比PR阴性肿瘤患者有更长的无进展生存期。这些保护作用的分子机制尚不清楚。为了研究在没有添加雌激素的情况下（即需要诱导PR的稳健表达），我们创建了ES-2 OC细胞，稳定表达载体控制或gfp标记的PR- b （GFP-PR）。黄体酮（R5020）刺激稳定表达GFP-PR的ES-2细胞诱导细胞衰老，其特征是细胞形态改变、存活时间延长、衰老相关的-半乳糖苷酶活性、G(1)细胞周期阻滞和细胞周期抑制剂p21以及叉头盒转录因子FOXO1的上调；这些结果在未修饰的ER+/PR+ PEO4 OC细胞中重复。PR-B和fox01在p21上游启动子的相同PRE-containing区域中检测到。p21的敲低通过FOXO1依赖性上调众多FOXO1靶基因（p15, p16, p27）导致分子补偿，并增加衰老速率。抑制FOXO1（含AS1842856）或稳定敲低FOXO1可抑制黄体酮诱导的p21表达，阻断黄体酮诱导的衰老。总的来说，这些发现支持了PR在OC细胞中作为肿瘤抑制因子的作用，它通过诱导fox01依赖性细胞衰老而表现出抑制作用。使用PR激动剂临床启动PR- fox01 -p21信号通路可能提供一种有用的策略来诱导不可逆的细胞周期阻滞，从而使OC细胞对现有的化疗敏感，作为两步联合治疗的一部分。
Loss of nuclear progesterone receptors (PR) and low circulating progesterone levels are associated with increased ovarian cancer (OC) risk. However, PR are abundantly expressed in a significant percentage of serous and endometrioid ovarian tumors; patients with PR+ tumors typically experience longer progression-free survival relative to those with PR-null tumors. The molecular mechanisms of these protective effects are poorly understood. To study PR action in OC in the absence of added estrogen (i.e., needed to induce robust PR expression), we created ES-2 OC cells stably expressing vector control or GFP-tagged PR-B (GFP-PR). Progestin (R5020) stimulation of ES-2 cells stably expressing GFP-PR induced cellular senescence characterized by altered cellular morphology, prolonged survival, senescence-associated -galactosidase activity, G(1) cell cycle arrest and upregulation of the cell cycle inhibitor, p21, as well as the Forkhead-box transcription factor, FOXO1; these results repeated in unmodified ER+/PR+ PEO4 OC cells. PR-B and FOXO1 were detected within the same PRE-containing regions of the p21 upstream promoter. Knockdown of p21 resulted in molecular compensation via FOXO1-dependent upregulation of numerous FOXO1 target genes (p15, p16, p27) and an increased rate of senescence. Inhibition of FOXO1 (with AS1842856) or stable FOXO1 knockdown inhibited progestin-induced p21 expression and blocked progestin-induced senescence. Overall, these findings support a role for PR as a tumor suppressor in OC cells, which exhibits inhibitory effects by inducing FOXO1-dependent cellular senescence. Clinical priming of the PR-FOXO1-p21 signaling pathway using PR agonists may provide a useful strategy to induce irreversible cell cycle arrest and thereby sensitize OC cells to existing chemotherapies as part of combination two-step therapies.