TRIM21 is a novel regulator of Par-4 in colon and pancreatic cancer cells.
TRIM21 is a novel regulator of Par-4 in colon and pancreatic cancer cells.
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DOI：
10.1080/15384047.2016.1252880
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发表时间：
2017-01-02
影响因子：
3.6
通讯作者：
Irby RB
中科院分区：
文献类型：
--
作者：
Nguyen JQ;Irby RB
前列腺细胞凋亡反应蛋白4（Par-4）是一种肿瘤抑制因子，已显示其在多种癌症中诱导癌细胞选择性凋亡。Par-4表达和活性的调节是一个相对未充分研究的领域，鉴定Par-4的新调节剂可作为新的治疗靶点。为了鉴定Par-4的新型调节剂，在结肠癌细胞中进行免疫共沉淀，并通过质谱法鉴定共沉淀的蛋白质。TRIM 21被鉴定为Par-4的新型相互作用伴侣，并且进一步显示出与Par-4内源性地以及通过其PRY-SPRY结构域相互作用。其他研究表明，TRIM 21下调Par-4水平以响应顺铂，并且TRIM 21可以增加结肠癌细胞对顺铂的抗性。此外，强制Par-4表达可以使胰腺癌细胞对顺铂敏感。最后，我们证明了TRIM 21表达预测胰腺癌患者的生存率。我们的工作突出了Par-4调节的新机制，并确定了胰腺癌的新预后标志物和潜在的治疗靶点。
The prostate apoptosis response protein 4 (Par-4) is a tumor-suppressor that has been shown to induce cancer-cell selective apoptosis in a variety of cancers. The regulation of Par-4 expression and activity is a relatively understudied area, and identifying novel regulators of Par-4 may serve as novel therapeutic targets. To identify novel regulators of Par-4, a co-immunoprecipitation was performed in colon cancer cells, and co-precipitated proteins were identified by mass-spectometry. TRIM21 was identified as a novel interacting partner of Par-4, and further shown to interact with Par-4 endogenously and through its PRY-SPRY domain. Additional studies show that TRIM21 downregulates Par-4 levels in response to cisplatin, and that TRIM21 can increase the resistance of colon cancer cells to cisplatin. Furthermore, forced Par-4 expression can sensitize pancreatic cancer cells to cisplatin. Finally, we demonstrate that TRIM21 expression predicts survival in pancreatic cancer patients. Our work highlights a novel mechanism of Par-4 regulation, and identifies a novel prognostic marker and potential therapeutic target for pancreatic cancer.