Dimethylfumarate Inhibits Colorectal Carcinoma Cell Proliferation: Evidence for Cell Cycle Arrest, Apoptosis and Autophagy
Dimethylfumarate Inhibits Colorectal Carcinoma Cell Proliferation: Evidence for Cell Cycle Arrest, Apoptosis and Autophagy
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DOI：
10.3390/cells8111329
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发表时间：
2019-11-01
期刊：
影响因子：
6
通讯作者：
Meissner, Markus
中科院分区：
文献类型：
--
作者：
Kaluzki, Irina;Hailemariam-Jahn, Tsige;Meissner, Markus
最近的研究证明，富马酸二甲酯（DMF）对多种癌症实体具有显著的抗增殖作用，恶性黑色素瘤为了探索其抗肿瘤的潜力，我们研究了DMF对人结肠癌细胞系的影响及其潜在的作用机制。用或不用DMF处理人结肠癌细胞系HT-29和人结肠直肠癌细胞系T84。主要通过溴脱氧尿苷（BrdU）和乳酸脱氢酶（LDH）测定、半胱天冬酶活化、流式细胞术、免疫荧光和免疫印迹分析DMF对增殖、细胞周期进程和细胞凋亡的影响。此外，还进行了放疗和化疗的联合治疗。DMF抑制两种细胞系中的细胞增殖。结果表明，DMF诱导细胞周期停滞在G 0/G1期，这伴随着p21的上调和细胞周期蛋白D1和细胞周期蛋白依赖性激酶（CDK）4的下调。此外，自噬相关蛋白的上调表明涉及自噬。此外，凋亡标志物的激活提供了凋亡参与的证据。我们的研究结果表明，DMF支持奥沙利铂的作用，在协同的方式和失败的协同辐射。我们证明DMF通过将细胞周期阻滞在G 0/G1期以及激活自噬和凋亡途径对结肠癌细胞具有明显的抗肿瘤作用，并与化疗协同作用。
Recent studies have proven that Dimethylfumarate (DMF) has a marked anti-proliferative impact on diverse cancer entities e.g., on malignant melanoma. To explore its anti-tumorigenic potential, we examined the effects of DMF on human colon carcinoma cell lines and the underlying mechanisms of action. Human colon cancer cell line HT-29 and human colorectal carcinoma cell line T84 were treated with or without DMF. Effects of DMF on proliferation, cell cycle progression, and apoptosis were analyzed mainly by Bromodeoxyuridine (BrdU)- and Lactatdehydrogenase (LDH)-assays, caspase activation, flowcytometry, immunofluorescence, and immunoblotting. In addition, combinational treatments with radiation and chemotherapy were performed. DMF inhibits cell proliferation in both cell lines. It was shown that DMF induces a cell cycle arrest in G0/G1 phase, which is accompanied by upregulation of p21 and downregulation of cyclin D1 and Cyclin dependent kinase (CDK)4. Furthermore, upregulation of autophagy associated proteins suggests that autophagy is involved. In addition, the activation of apoptotic markers provides evidence that apoptosis is involved. Our results show that DMF supports the action of oxaliplatin in a synergetic manner and failed synergy with radiation. We demonstrated that DMF has distinct anti-tumorigenic, cell dependent effects on colon cancer cells by arresting cell cycle in G0/G1 phase as well as activating both the autophagic and apoptotic pathways and synergizes with chemotherapy.