PC-1/PrLZ confers resistance to rapamycin in prostate cancer cells through increased 4E-BP1 stability.
PC-1/PrLZ confers resistance to rapamycin in prostate cancer cells through increased 4E-BP1 stability.
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PC-1/PrLZ 通过增加 4E-BP1 稳定性赋予前列腺癌细胞对雷帕霉素的耐药性。
DOI：
10.18632/oncotarget.3931
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发表时间：
2015-08-21
期刊：
影响因子：
--
通讯作者：
Li S
中科院分区：
文献类型：
--
作者：
Yu L;Shang ZF;Wang J;Wang H;Huang F;Zhang Z;Wang Y;Zhou J;Li S
改善晚期PCa治疗的一个重要策略是靶向治疗和化疗相结合。PC-1是一种前列腺亮氨酸拉链基因(PrLZ)，作为雄激素诱导基因在前列腺组织中特异表达，在晚期前列腺癌中表达上调。最近的研究证实，PC-1的表达促进了前列腺癌的生长和雄激素非依赖性进展。然而，这种情况是如何发生的，以及是否可以被用作生物标志物，目前还不确定。在这里，我们报告了PC-1的过表达通过拮抗雷帕霉素诱导的细胞停滞和自噬(在PC-1缺陷(SHPC-1)C4-2细胞中观察到雷帕霉素敏感性)，使PCa细胞对雷帕霉素治疗产生抵抗。对PC-1过表达和下调的PCa细胞mTOR通路的分析表明，真核细胞起始因子4E结合蛋白1(4E-BP1)受PC-1的高度调控。免疫组织化学分析表明，4E-BP1的上调与PC-1在前列腺癌和前列腺癌细胞中的表达增加有关。此外，PC-1与4E-BP1直接相互作用，通过抑制其泛素化和蛋白酶体降解来稳定4E-BP1蛋白。因此，PC-1是4E-BP1的一种新的调节因子，我们的工作提示了PC-1增强PCa细胞存活和恶性进展以及增加化疗耐药性的潜在机制。因此，PC-1-4E-BP1的相互作用可能是治疗晚期前列腺癌的一个治疗靶点。
An important strategy for improving advanced PCa treatment is targeted therapies combined with chemotherapy. PC-1, a prostate Leucine Zipper gene (PrLZ), is specifically expressed in prostate tissue as an androgen-induced gene and is up-regulated in advanced PCa. Recent work confirmed that PC-1 expression promotes PCa growth and androgen-independent progression. However, how this occurs and whether this can be used as a biomarker is uncertain. Here, we report that PC-1 overexpression confers PCa cells resistance to rapamycin treatment by antagonizing rapamycin-induced cytostasis and autophagy (rapamycin-sensitivity was observed in PC-1-deficient (shPC-1) C4-2 cells). Analysis of the mTOR pathway in PCa cells with PC-1 overexpressed and depressed revealed that eukaryotic initiation factor 4E-binding protein 1(4E-BP1) was highly regulated by PC-1. Immunohistochemistry assays indicated that 4E-BP1 up-regulation correlates with increased PC-1 expression in human prostate tumors and in PCa cells. Furthermore, PC-1 interacts directly with 4E-BP1 and stabilizes 4E-BP1 protein via inhibition of its ubiquitination and proteasomal degradation. Thus, PC-1 is a novel regulator of 4E-BP1 and our work suggests a potential mechanism through which PC-1 enhances PCa cell survival and malignant progression and increases chemoresistance. Thus, the PC-1-4E-BP1 interaction may represent a therapeutic target for treating advanced PCa.