Modulation of p73 isoforms expression induces anti-proliferative and pro-apoptotic activity in mantle cell lymphoma independent of p53 status.
Modulation of p73 isoforms expression induces anti-proliferative and pro-apoptotic activity in mantle cell lymphoma independent of p53 status.
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DOI：
10.3109/10428194.2016.1165814
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发表时间：
2016-12
影响因子：
2.6
通讯作者：
Dave BJ
中科院分区：
文献类型：
--
作者：
Hassan HM;Varney ML;Chaturvedi NK;Joshi SS;Weisenburger DD;Singh RK;Dave BJ
套细胞淋巴瘤（MCL）的特点是临床病程具有侵袭性，易复发，生存率低。p53通路经常失调，p53状态预测临床结果。在本报告中，我们研究了双氯芬酸对MCL中p73亚型的调节是否会抑制细胞生长、诱导细胞凋亡和/或细胞周期阻滞。使用MCL患者分离的野生型p53 [Granta-519和JVM-2]、突变型p53 [Jeko-1和Mino-1]表达细胞、治疗耐药细胞系和原代人细胞。过表达促凋亡的TAp73促进MCL细胞凋亡。双氯芬酸诱导浓度和持续时间依赖性的TAp73增加，细胞周期阻滞，细胞死亡，并抑制独立于p53状态的MCL细胞生长。双氯芬酸治疗与半胱天冬酶3、7和8的活性增加以及p53转录靶基因的诱导相关。这些研究证明了双氯芬酸作为MCL独立于p53状态的新型治疗剂的潜力。
Mantle cell lymphoma (MCL) is characterized by a clinically aggressive course with frequent relapse and poor survival. The p53 pathway is frequently dysregulated and p53 status predicts clinical outcome. In this report, we investigated whether modulation of p73 isoforms by diclofenac inhibits cell growth, induces apoptosis and/or cell cycle arrest in MCL relative to p53 status. Wild-type p53 [Granta-519 and JVM-2], mutant p53 [Jeko-1 and Mino-1] expressing cells, therapy resistant cell lines, and primary human cells isolated from MCL patients were used. Overexpression of pro-apoptotic TAp73 enhanced MCL cell apoptosis. Diclofenac induced a concentration- and duration-dependent increase in TAp73, cell cycle arrest, cell death, and inhibited MCL cell growth independent of p53 status. Diclofenac treatment was associated with increased activity of caspases 3, 7, and 8 and induction of p53 transcriptional target genes. These studies demonstrate the potential for diclofenac as novel therapeutic agent in MCL independent of p53 status.