Protein kinase D2 is a novel regulator of glioblastoma growth and tumor formation
Protein kinase D2 is a novel regulator of glioblastoma growth and tumor formation
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DOI：
10.1093/neuonc/nor084
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发表时间：
2011-07-01
期刊：
影响因子：
15.9
通讯作者：
Seufferlein, Thomas
中科院分区：
文献类型：
--
作者：
Azoitei, Ninel;Kleger, Alexander;Seufferlein, Thomas
多形性胶质母细胞瘤是一种高度侵袭性的中枢神经系统肿瘤，其预后很差，部分原因是其对放疗和化疗的抵抗力。蛋白激酶C（PKC）家族的丝氨酸/苏氨酸激酶已被牵连在多形性胶质母细胞瘤的形成和增殖。蛋白激酶D（PKD）家族成员，包括PKD 1、PKD-2和PKD-3，是PKC的重要下游靶点，在胶质母细胞瘤生长中发挥重要作用。PKD 2在低级别和高级别人脑胶质瘤中均高度表达。PKD 2阳性肿瘤细胞数随胶质瘤分级增加而增加（P <0.001）。PKD 2也表达在CD 133阳性胶质母细胞瘤干细胞和各种胶质母细胞瘤细胞系中，其中激酶被发现是组成性活性的。通过药理学抑制剂抑制PKD导致胶质母细胞瘤增殖的实质性抑制。此外，特异性消耗PKD 2的siRNA导致锚定依赖性和非依赖性增殖的显着抑制和胶质母细胞瘤细胞在G 0/G1期的积累，伴随着下调细胞周期蛋白D1的表达。此外，PKD 2耗尽的胶质母细胞瘤细胞在鸡绒毛尿囊膜上表现出体内肿瘤形成的显著减少。这些发现将PKD 2鉴定为体外和体内胶质母细胞瘤细胞生长的新介质，从而作为这种毁灭性疾病的潜在治疗靶点。
Glioblastoma multiforme, a highly aggressive tumor of the central nervous system, has a dismal prognosis that is due in part to its resistance to radio- and chemotherapy. The protein kinase C (PKC) family of serine threonine kinases has been implicated in the formation and proliferation of glioblastoma multiforme. Members of the protein kinase D (PKD) family, which consists of PKD1, -2 and, -3, are prominent downstream targets of PKCs and could play a major role in glioblastoma growth. PKD2 was highly expressed in both low-grade and high-grade human gliomas. The number of PKD2-positive tumor cells increased with glioma grading (P < .001). PKD2 was also expressed in CD133-positive glioblastoma stem cells and various glioblastoma cell lines in which the kinase was found to be constitutively active. Inhibition of PKDs by pharmacological inhibitors resulted in substantial inhibition of glioblastoma proliferation. Furthermore, specific depletion of PKD2 by siRNA resulted in a marked inhibition of anchorage-dependent and -independent proliferation and an accumulation of glioblastoma cells in G0/G1, accompanied by a down-regulation of cyclin D1 expression. In addition, PKD2-depleted glioblastoma cells exhibited substantially reduced tumor formation in vivo on chicken chorioallantoic membranes. These findings identify PKD2 as a novel mediator of glioblastoma cell growth in vitro and in vivo and thereby as a potential therapeutic target for this devastating disease.