Pim2 is required for maintaining multiple myeloma cell growth through modulating TSC2 phosphorylation
Pim2 is required for maintaining multiple myeloma cell growth through modulating TSC2 phosphorylation
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DOI：
10.1182/blood-2013-01-481457
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发表时间：
2013-08-29
期刊：
影响因子：
20.3
通讯作者：
Garcia, Pablo D.
中科院分区：
文献类型：
--
作者：
Lu, Jing;Zavorotinskaya, Tatiana;Garcia, Pablo D.
多发性骨髓瘤（MM）是第二常见的血液系统恶性肿瘤。尽管最近的治疗进展，它仍然无法治愈。在这里，我们报告说，Pim 2激酶的表达是高度升高的MM细胞，并证明它是需要MM细胞增殖。通过短发夹RNA或通过有效的和选择性的小分子抑制剂对Pim 2活性的功能性干扰导致MM细胞增殖的显著抑制。Pim抑制导致雷帕霉素C1（mTOR-C1）活性的哺乳动物靶标的显著降低，这对于细胞增殖至关重要。我们鉴定了mTOR-C1的负调节因子TSC 2作为新型Pim 2底物，并表明Pim 2直接磷酸化Ser-1798上的TSC 2，并解除了TSC 2对mTOR-C1的抑制。这些发现支持Pim 2作为MM的有希望的治疗靶点，并定义了驱动MM增殖的新型Pim 2-TSC 2-mTOR-C1途径。
Multiple myeloma (MM) is the second most common hematologic malignancy. Despite recent treatment advances, it remains incurable. Here, we report that Pim2 kinase expression is highly elevated in MM cells and demonstrate that it is required for MM cell proliferation. Functional interference of Pim2 activity either by short hairpin RNAs or by a potent and selective small-molecule inhibitor leads to significant inhibition of MM cell proliferation. Pim inhibition results in a significant decrease of mammalian target of rapamycin C1 (mTOR-C1) activity, which is critical for cell proliferation. We identify TSC2, a negative regulator of mTOR-C1, as a novel Pim2 substrate and show that Pim2 directly phosphorylates TSC2 on Ser-1798 and relieves the suppression of TSC2 on mTOR-C1. These findings support Pim2 as a promising therapeutic target for MM and define a novel Pim2-TSC2-mTOR-C1 pathway that drives MM proliferation.