Cancer Cell Biology Group, Institut Universitari d'Investigació en Ciències de la Salut (IUNICS), Universitat de les Illes Balears, Palma, Illes Balears, Crta Valldemossa km 7Æ5. E-07122 Palma, Illes Balears, Spain.
Br J Haematol. 2012 Feb;156(3):334-45. doi: 10.1111/j.1365-2141.2011.08951.x. Epub 2011 Nov 23.
The FOXO3 (Forkhead/winged helix box class O 3) transcription factor is a crucial regulator of haematopoietic cell fate that controls proliferation and apoptosis, among other processes. Despite the central role of FOXO3 as a tumour suppressor and phosphatidylinositol 3-kinase (PI3K)/AKT effector, little is known about its involvement in mantle cell lymphoma (MCL) biology. This study investigated the expression and activity of FOXO3 in MCL cell lines and in primary cultures. We analysed the expression of key FOXO regulators and targets, and studied the effect of modulators of FOXO function on cell viability and apoptosis. FOXO3 was constitutively inactivated in MCL cell lines, and showed cytoplasmic localization in patient-derived cells. PI3K and AKT, but not mammalian target of rapamycin (mTOR), inhibitors induced FOXO3 nuclear translocation and activation in correlation with their impact on MCL proliferation and survival. Moreover, FOXO3-defective cells were resistant to PI3K/AKT inhibitors. Reactivation of FOXO function with a nuclear export inhibitor had a profound effect on cell viability, consistent with FOXO3 nuclear accumulation. Interestingly, inhibition of FOXO3 nuclear export enhanced the effect of doxorubicin. Taken together, our results confirm that FOXO3 is a relevant regulator of proliferation and apoptosis in MCL, and suggest that reactivation of FOXO3 function might be a useful therapeutic strategy in MCL patients.
FOXO3（叉头/翼状螺旋转录因子 O 家族 3）转录因子是造血细胞命运的关键调节因子，控制增殖和凋亡等过程。尽管 FOXO3 作为肿瘤抑制因子和磷脂酰肌醇 3-激酶（PI3K）/AKT 效应物发挥着核心作用，但人们对其在套细胞淋巴瘤（MCL）生物学中的作用知之甚少。本研究调查了 FOXO3 在 MCL 细胞系和原代培养物中的表达和活性。我们分析了关键 FOXO 调节因子和靶标的表达，并研究了 FOXO 功能调节剂对细胞活力和凋亡的影响。FOXO3 在 MCL 细胞系中持续失活，并在源自患者的细胞中显示出细胞质定位。PI3K 和 AKT，但不是雷帕霉素（mTOR）的哺乳动物靶标抑制剂，诱导 FOXO3 核易位和激活，与它们对 MCL 增殖和存活的影响相关。此外，FOXO3 缺陷细胞对 PI3K/AKT 抑制剂具有抗性。用核输出抑制剂重新激活 FOXO 功能对细胞活力有深远影响，与 FOXO3 核积累一致。有趣的是，抑制 FOXO3 核输出增强了多柔比星的作用。总之，我们的结果证实 FOXO3 是 MCL 增殖和凋亡的重要调节因子，并表明重新激活 FOXO3 功能可能是 MCL 患者的一种有用的治疗策略。
