Abstract:
Epithelial ovarian cancer (EOC) is deadliest gynecological malignancy with poor prognosis and patient survival. Despite development of several therapeutic interventions such as poly-ADP ribose polymerase (PARP) inhibitors, EOC remains unmanageable and discovery of novel early detection biomarkers and treatment targets are highly warranted. Although neuroendocrine differentiation (NED) is implicated in different human cancers including prostate adenocarcinoma and lung cancer, mechanistic studies concerning NED of epithelial ovarian cancer are lacking. We report that Aurora kinase A drives NED of epithelial ovarian cancer in an ERK1/2-dependent manner and pharmacological and genetic inhibition of Aurora kinase A suppress NED of ovarian cancer. Moreover, we demonstrate that protein kinase D2 positively regulated Aurora kinase A to drive NED. Overexpression of catalytically active PKD2 drives NED and collectively, PKD2 cross talks with Aurora kinase A/ERK1/2 signalling axis to positively regulate NED of EOC. PKD2/Aurora kinase A/ERK1/2 signalling axis is a novel therapeutic target against neuroendocrine differentiated EOC.
摘要:
上皮性卵巢癌(EOC)是最致命的妇科恶性肿瘤,预后和患者生存率较差。尽管开发了几种治疗干预措施,如聚ADP核糖聚合酶(PARP)抑制剂,EOC仍然难以管理,并且非常有必要发现新的早期检测生物标志物和治疗靶标。尽管神经内分泌分化(NED)涉及不同的人类癌症,包括前列腺癌和肺癌,缺乏关于上皮性卵巢癌NED的机制研究。我们报道Aurora激酶A以ERK1/2依赖性方式驱动上皮性卵巢癌的NED,Aurora激酶A的药理和遗传抑制抑制卵巢癌的NED。此外,我们证明蛋白激酶D2正调节极光激酶A驱动NED。催化活性PKD2的过表达驱动NED和集体,PKD2与Aurora激酶A/ERK1/2信号轴交叉对话以积极调节EOC的NED。PKD2/Aurora激酶A/ERK1/2信号轴是针对神经内分泌分化型EOC的新型治疗靶标。