Muniyan Sakthivel, Vengoji Raghupathy, Nimmakayala Rama Krishna, Seshacharyulu Parthasarathy, Perumalsamy Balaji, Alsafwani Zahraa Wajih, Kakar Sham S, Smith Lynette M, Shonka Nicole, Teply Benjamin A, Lele Subodh M, Ponnusamy Moorthy P, Batra Surinder K
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Cancer Lett. 2025 Jan 28;609:217355. doi: 10.1016/j.canlet.2024.217355. Epub 2024 Nov 26.
Advanced prostate cancer (PCa) remains a significant clinical challenge, and docetaxel plays a significant role in disease management. Despite the efficacy of docetaxel as a first-line chemotherapy, resistance often develops. We developed three clinically relevant in vitro PCa cell models and transcriptomic analysis identified that the Paf1/RNA polymerase II complex component (PAF1)-associated pluripotent-transcription factor (TF), SOX2, plays a crucial role in docetaxel resistance. The cancer stem cell (CSC) transcriptional master regulator PAF1 is significantly higher in PCa cell lines, tumor tissues, and docetaxel resistant (DR) PCa cells than in age-matched control cells. To determine the molecular underlying and functional characteristics of PAF1 in resistance mechanisms, we performed coimmunoprecipitation, embryonic stem cell network proteins, in vitro tumor-initiating ability, and 3D multicellular organoid growth using PAF1 knockdown cells. Tet-inducible PAF1 depletion reduced the drug-efflux phenotype, tumor-initiating frequencies, and three-dimensional organoid growth of the docetaxel-resistant PCa cell lines. Functional studies also showed restoration of docetaxel sensitivity in a 3D tumorsphere model upon PAF1 depletion. PAF1 depletion was also associated with decreased pluripotent TFs and other CSC markers. This study provides a novel regulatory mechanism of docetaxel resistance in PCa through PAF1.
晚期前列腺癌（PCa）仍然是一个重大的临床挑战，多西他赛在疾病管理中发挥着重要作用。尽管多西他赛作为一线化疗药物具有疗效，但耐药性往往会出现。我们建立了三种临床相关的体外PCa细胞模型，转录组分析确定与Paf1/RNA聚合酶II复合物成分（PAF1）相关的多能转录因子（TF）SOX2在多西他赛耐药中起关键作用。癌症干细胞（CSC）转录主调节因子PAF1在PCa细胞系、肿瘤组织和多西他赛耐药（DR）PCa细胞中显著高于年龄匹配的对照细胞。为了确定PAF1在耐药机制中的分子基础和功能特征，我们使用PAF1敲低细胞进行了免疫共沉淀、胚胎干细胞网络蛋白、体外肿瘤起始能力和三维多细胞类器官生长实验。四环素诱导的PAF1缺失降低了多西他赛耐药PCa细胞系的药物外排表型、肿瘤起始频率和三维类器官生长。功能研究还表明，在PAF1缺失后，三维肿瘤球模型中多西他赛敏感性得以恢复。PAF1缺失还与多能转录因子和其他CSC标志物的减少有关。本研究通过PAF1提供了一种PCa中多西他赛耐药的新调控机制。
