CDK9 is a prognostic marker and therapeutic target in pancreatic cancer
CDK9 is a prognostic marker and therapeutic target in pancreatic cancer
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DOI：
10.1177/1010428317694304
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发表时间：
2017-02-01
期刊：
影响因子：
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通讯作者：
Lemke, Johannes
中科院分区：
文献类型：
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作者：
Kretz, Anna-Laura;Schaum, Monika;Lemke, Johannes
尽管近年来在诊断和治疗方面取得了进展，但胰腺癌的预后仍然很差。除了有效的预后标记物外，迫切需要新的治疗方法。细胞周期蛋白依赖性蛋白激酶家族由20个蛋白组成，它们通过促进癌细胞的增殖、迁移、侵袭和抗凋亡而导致恶性肿瘤。在这项工作中，我们研究了CDK9在胰腺癌中的作用。免疫组织化学分析CDK9在胰腺癌患者肿瘤组织和正常组织中的表达，发现CDK9在胰腺癌组织中过表达。此外，肿瘤组织中CDK9的高表达与显著缩短生存期有关，尤其是在分化良好的肿瘤中。此外，通过细胞存活率、长期存活和诱导细胞凋亡的分析，并通过Western blotting和流式细胞术对选择性抑制CDK9对胰腺癌细胞的治疗作用进行了评价。SNS-032对CDK9的药理抑制显著降低了胰腺癌细胞的细胞存活率，并有效地抑制了长期存活。对CDK9的作用机制分析表明，CDK9抑制通过抑制抗凋亡蛋白诱导细胞凋亡和细胞周期停滞，并呈时间依赖性。此外，抑制CDK9有效地增强了化疗药物对胰腺癌细胞的治疗效果。综上所述，我们认为CDK9是胰腺癌的一个负向预后标志物。此外，药物抑制CDK9是治疗胰腺癌的一种新的、有前途的方法。
Despite recent advances in diagnosis and therapy, prognosis of pancreatic cancer still remains very poor. Besides valid prognostic markers, novel therapeutic approaches are urgently needed. The family of cyclin-dependent kinases comprises 20 kinases which contribute to malignancy by promoting proliferation, migration, invasion, and apoptotic resistance of cancer cells. In this work, we investigated the role of CDK9 in pancreatic cancer. Immunohistochemical analysis of CDK9 expression in tumor and normal tissue of pancreatic cancer patients revealed an overexpression of CDK9 in pancreatic cancer tissue. In addition, high CDK9 expression in tumor tissue is associated with significantly shortened survival, especially in well-differentiated tumors. Moreover, the therapeutic potential of selective CDK9 inhibition on pancreatic cancer cells was evaluated by analysis of cell viability, long-term survival, and induction of apoptosis and characterized by western blotting and flow cytometry. Pharmacological CDK9 inhibition by SNS-032 drastically reduced cell viability in pancreatic cancer cells and potently suppressed long-term survival. Analyzing the mechanism of action revealed that CDK9 inhibition induced apoptosis and cell cycle arrest in a time-dependent manner by suppression of anti-apoptotic proteins. Furthermore, CDK9 inhibition potently enhances the therapeutic effect of chemotherapeutics in pancreatic cancer cells. In conclusion, we identified CDK9 as a negative prognostic marker in pancreatic cancer. Furthermore, pharmacological CDK9 inhibition is a novel and promising therapeutic approach for pancreatic cancer.