Shen Xiao, Kretz Anna-Laura, Schneider Sandra, Knippschild Uwe, Henne-Bruns Doris, Kornmann Marko, Lemke Johannes, Traub Benno
Department of General and Visceral Surgery, Ulm University Hospital, Albert-Einstein-Allee 23, 89081 Ulm, Germany.
Biomedicines. 2023 Mar 16;11(3):928. doi: 10.3390/biomedicines11030928.
Treatment options for colorectal cancer (CRC), especially in advanced stages are still insufficient. There, the discovery of Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) was a bright spot. However, most cancers show resistance toward apoptotic signals. Cyclin-dependent kinase 9 (CDK9) plays a crucial role in cell cycle progression in most tissues. We recently demonstrated the role of CDK9 in mediating TRAIL resistance. In this work, we investigated the role of CDK9 in colorectal cancer. Immunohistochemical analysis of CDK9 expression in cancer and normal tissues of CRC specimens was performed. The effect of selective CDK9 inhibition in combination with TRAIL on CRC cells was analyzed via cell viability, colony formation, and induction of apoptosis by flow cytometry. The mechanism of action was conducted via western blotting. We now have confirmed overexpression of CDK9 in cancer tissues, with low expression associated with poorer survival in a subset of CRC patients. In-vitro, CDK9 inhibition could strongly promote TRAIL-induced cell death in TRAIL-resistant CRC cells. Mechanistically, CDK9 inhibition induced apoptosis by downregulation of antiapoptotic proteins, myeloid leukemia cell differentiation protein 1 (Mcl-1) and FLICE-inhibitory protein (c-FLIP). Overall, we identified CDK9 as a prognostic marker and combined CDK9 inhibition and TRAIL as a novel and promising therapeutic approaches for colorectal cancer.
结直肠癌（CRC）的治疗选择，尤其是晚期患者的治疗选择仍然不足。在这方面，肿瘤坏死因子（TNF）相关凋亡诱导配体（TRAIL）的发现是一个亮点。然而，大多数癌症对凋亡信号具有抗性。细胞周期蛋白依赖性激酶9（CDK9）在大多数组织的细胞周期进程中起着关键作用。我们最近证明了CDK9在介导TRAIL抗性中的作用。在这项工作中，我们研究了CDK9在结直肠癌中的作用。对CRC标本的癌组织和正常组织中的CDK9表达进行了免疫组织化学分析。通过细胞活力、集落形成以及流式细胞术检测凋亡诱导情况，分析了选择性CDK9抑制与TRAIL联合使用对CRC细胞的影响。通过蛋白质印迹法研究其作用机制。我们现已证实癌组织中CDK9过表达，在一部分CRC患者中，低表达与较差的生存率相关。在体外，CDK9抑制可强烈促进TRAIL抗性CRC细胞中TRAIL诱导的细胞死亡。从机制上讲，CDK9抑制通过下调抗凋亡蛋白、髓样白血病细胞分化蛋白1（Mcl-1）和FLICE抑制蛋白（c-FLIP）诱导凋亡。总体而言，我们确定CDK9为一种预后标志物，并将CDK9抑制与TRAIL联合使用作为结直肠癌一种新的、有前景的治疗方法。
