Sachdeva Abha, Roy Adhiraj, Mandal Supratim
Amity Institute of Molecular Medicine and Stem Cell Research, Amity University, Sector 125, Noida, Uttar Pradesh, 201303, India.
Department of Microbiology, University of Kalyani, Kalyani, Nadia, West Bengal, 741235, India.
Mol Cell Biochem. 2025 Jan;480(1):535-547. doi: 10.1007/s11010-024-04986-2. Epub 2024 Apr 1.
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.
上皮性卵巢癌（EOC）是最致命的妇科恶性肿瘤，预后较差，患者生存率低。尽管已经开发了多种治疗干预措施，如聚ADP核糖聚合酶（PARP）抑制剂，但EOC仍然难以治疗，因此迫切需要发现新的早期检测生物标志物和治疗靶点。虽然神经内分泌分化（NED）与包括前列腺腺癌和肺癌在内的不同人类癌症有关，但关于上皮性卵巢癌NED的机制研究尚缺。我们报告称，极光激酶A以ERK1/2依赖性方式驱动上皮性卵巢癌的NED，对极光激酶A的药理和基因抑制可抑制卵巢癌的NED。此外，我们证明蛋白激酶D2正向调节极光激酶A以驱动NED。催化活性PKD2的过表达驱动NED，总体而言，PKD2与极光激酶A/ERK1/2信号轴相互作用，以正向调节EOC的NED。PKD2/极光激酶A/ERK1/2信号轴是针对神经内分泌分化型EOC的新型治疗靶点。
