Pim1 promotes human prostate cancer cell tumorigenicity and c-MYC transcriptional activity
Pim1 promotes human prostate cancer cell tumorigenicity and c-MYC transcriptional activity
复制标题
DOI：
10.1186/1471-2407-10-248
复制
发表时间：
2010-06-01
期刊：
影响因子：
3.8
通讯作者：
Abdulkadir, Sarki A.
中科院分区：
文献类型：
--
作者：
Kim, Jongchan;Roh, Meejeon;Abdulkadir, Sarki A.
背景：丝氨酸/苏氨酸激酶PIM1被认为是多种人类癌症的癌基因，包括淋巴瘤、胃癌、结直肠癌和前列腺癌。在小鼠模型中，已知Pim1与c-Myc合作促进肿瘤发生。然而，对于Pim1过表达在人前列腺癌细胞中的致瘤潜能的体内分析一直是有限的。方法：我们在良性(RWPE1)、雄激素依赖癌(LNCaP)和雄激素非依赖性癌(DU145)等三个不同疾病阶段的人前列腺细胞系中过表达Pim1。然后，我们通过报告分析和可诱导的MYC-ER系统的基因表达谱分析了体外和体内的致瘤性以及Pim1过表达对c-myc转录活性的影响。为了验证Pim1通过调节c-myc转录活性来诱导c-myc的致瘤性和靶基因的表达，我们使用小分子抑制剂(10058-F4)或RNA干扰来抑制c-myc。结果：Pim1的过度表达不足以将良性的RWPE1细胞转化为恶性，尽管它在体内作为异种移植瘤生长时促进了细胞的增殖。然而，Pim1的表达增强了人前列腺癌LNCaP和DU145细胞的体外和体内致瘤能力。报告分析表明，在表达Pim1的细胞中，c-myc的转录活性增加，mRNA表达谱表明，很大一部分c-myc靶基因也受到Pim1表达的调控。C-myc抑制剂10058-F4抑制表达Pim1的前列腺癌细胞的致瘤性。有趣的是，10058-F4处理也导致了Pim1蛋白的减少，但不是mR-NA。用短发夹状RNA敲除c-myc逆转了Pim1对Pim1/myc靶基因的影响。结论：我们的结果提示，尽管Pim1在不同的细胞系中表现出不同的致癌活性，但它在促进前列腺癌的发生中具有体内作用。PIM1至少部分地通过增强c-myc转录活性来促进肿瘤的发生。我们还发现，用c-myc抑制剂10058-F4处理细胞会导致Pim1蛋白水平的降低。
Background: The serine/threonine kinase PIM1 has been implicated as an oncogene in various human cancers including lymphomas, gastric, colorectal and prostate carcinomas. In mouse models, Pim1 is known to cooperate with c-Myc to promote tumorigenicity. However, there has been limited analysis of the tumorigenic potential of Pim1 overexpression in benign and malignant human prostate cancer cells in vivo.Methods: We overexpressed Pim1 in three human prostate cell lines representing different disease stages including benign (RWPE1), androgen-dependent cancer (LNCaP) and androgen-independent cancer (DU145). We then analyzed in vitro and in vivo tumorigenicity as well as the effect of Pim1 overexpression on c-MYC transcriptional activity by reporter assays and gene expression profiling using an inducible MYC-ER system. To validate that Pim1 induces tumorigenicity and target gene expression by modulating c-MYC transcriptional activity, we inhibited c-MYC using a small molecule inhibitor (10058-F4) or RNA interference.Results: Overexpression of Pim1 alone was not sufficient to convert the benign RWPE1 cell to malignancy although it enhanced their proliferation rates when grown as xenografts in vivo. However, Pim1 expression enhanced the in vitro and in vivo tumorigenic potentials of the human prostate cancer cell lines LNCaP and DU145. Reporter assays revealed increased c-MYC transcriptional activity in Pim1-expressing cells and mRNA expression profiling demonstrated that a large fraction of c-MYC target genes were also regulated by Pim1 expression. The c-MYC inhibitor 10058-F4 suppressed the tumorigenicity of Pim1-expressing prostate cancer cells. Interestingly, 10058-F4 treatment also led to a reduction of Pim1 protein but not mRNA. Knocking-down c-MYC using short hairpin RNA reversed the effects of Pim1 on Pim1/MYC target genes.Conclusion: Our results suggest an in vivo role of Pim1 in promoting prostate tumorigenesis although it displayed distinct oncogenic activities depending on the disease stage of the cell line. Pim1 promotes tumorigenicity at least in part by enhancing c-MYC transcriptional activity. We also made the novel discovery that treatment of cells with the c-MYC inhibitor 10058-F4 leads to a reduction in Pim1 protein levels.