PKC ζ-mTOR pathway:: a new target for rituximab therapy in follicular lymphoma
PKC ζ-mTOR pathway:: a new target for rituximab therapy in follicular lymphoma
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DOI：
10.1182/blood-2007-04-085092
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发表时间：
2008-01-01
期刊：
影响因子：
20.3
通讯作者：
Bezombes, Christine
中科院分区：
文献类型：
--
作者：
Leseux, Ludivine;Laurent, Guy;Bezombes, Christine
以前的研究已经证明，在恶性B细胞中，利妥昔单抗引起一个复杂的信号网络，目前还不完全清楚，这些信号网络有助于发挥其抗肿瘤作用。在此背景下，我们研究了蛋白激酶C Zeta(PKC Zeta)，一种非典型的PKC亚型，在细胞对利妥昔单抗的反应中所起的作用。我们发现滤泡性淋巴瘤细胞与非恶性B细胞相比，PKC Zeta的表达和活性水平增加，并且该酶通过刺激Raf-1激酶的活性而成为经典的MAPK模块的关键调节因子。PKC Zeta似乎通过MAPK依赖的机制对叶状淋巴瘤细胞mTOR的异常调节起重要作用。利妥昔单抗可抑制这些细胞中的PKC Zeta/MAPK/mTOR模块，但在其他B细胞淋巴瘤中则不能。重要的是，一种结构性活性形式的PKC Zeta的表达导致了这些细胞对利妥昔单抗的有效保护。总之，我们的研究描述了滤泡细胞淋巴瘤mTOR通路的一个新的调节成分，并证明PKC Zeta是利妥昔单抗的靶点。因此，PKC Zeta可代表利妥昔单抗疗效的重要参数，并有望成为滤泡性淋巴瘤未来靶向治疗的靶点。
Previous studies have documented that, in malignant B cells, rituximab elicits a complex and not yet totally understood signaling network contributing to its antitumor effect. In this context, we investigated the role of protein kinase C zeta(PKC zeta), an atypical PKC isoform, in the cellular response to rituximab. We found that follicular lymphoma cells displayed an increase in PKC zeta expression and activity levels, compared with nonmalignant B cells, and that this enzyme was a critical regulator of the classical MAPK module by stimulating Raf-1 kinase activity. PKC zeta appeared to be a significant contributor of abnormal mTOR regulation in folilcular lymphoma cells through a MAPK-dependent mechanism. Rituximab was found to inhibit the PKC zeta/MAPK/mTOR module in these cells but not in other B-cell lymphomas. Importantly, the expression of a constitutively active form of PKC zeta resulted in an efficient protection of these cells toward rituximab. Altogether, our study describes a new regulatory component of mTOR pathway in follicular cell lymphoma and demonstrates that PKC zeta is a target for rituximab. Therefore, PKC zeta could represent an important parameter for rituximab efficacy and a promising target for future targeted therapy in follicular lymphoma.