Suppression of lung metastases by the CD26/DPP4 inhibitor Vildagliptin in mice
Suppression of lung metastases by the CD26/DPP4 inhibitor Vildagliptin in mice
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DOI：
10.1007/s10585-015-9736-z
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发表时间：
2015-10-01
影响因子：
4
通讯作者：
Jungraithmayr, Wolfgang
中科院分区：
文献类型：
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作者：
Jang, Jae-Hwi;Baerts, Lesley;Jungraithmayr, Wolfgang
如今，转移瘤而非原发肿瘤决定着患者的生存期。结直肠癌是最常见的原发恶性肿瘤之一，这类肿瘤的特点是具有向肺和肝转移的高倾向性。CD26/DPP4是一种具有酶功能的跨膜分子，可裂解生物活性肽。近期，CD26/DPP4已成为癌症研究的焦点，并且有研究表明CD26/DPP4阳性癌细胞显示出更强的转移活性。在此，我们测试了CD26/DPP4抑制剂维格列汀是否能抑制小鼠结直肠癌肺转移的发生和生长。这种CD26/DPP4抑制剂被用于小鼠（C57BL/6）结直肠癌肺转移模型，该模型是通过静脉注射同基因细胞系MC38建立的。为了进行机制分析，使用了皮下肿瘤模型。维格列汀治疗显著抑制了肺转移的发生率和生长。自噬标记物（LC3、p62和ATF4）减少，细胞凋亡增加（TUNEL、pH3/Ki - 76），细胞周期调节因子pCDC2受到抑制。总之，我们在此表明维格列汀通过下调自噬产生抗肿瘤作用，从而导致细胞凋亡增加和细胞周期调节。因此，我们提议对维格列汀进行评估，将其作为治疗结直肠癌肺转移的一种新的治疗方法。
Metastases rather than primary cancers determine nowadays the survival of patients. One of the most common primary malignancies is colorectal cancer and this type of tumor is characterized by a high tendency to spread metastases to the lung and liver. CD26/DPP4 is a transmembrane molecule with enzymatic functions which cleaves biologically active peptides. Recently, CD26/DPP4 has become the focus of cancer research and it was shown that CD26/DPP4-positive cancer cells display increased metastatic activity. Here, we tested if the CD26/DPP4-inhibitor Vildagliptin suppresses the development and growth of mouse colorectal lung metastases. This inhibitor of CD26/DPP4 was employed on mouse (C57BL/6) colorectal lung metastases, established by intravenous injection of the syngeneic cell line MC38. For mechanistic analysis, a subcutaneous tumor model was used. The treatment with Vildagliptin significantly suppressed both, the incidence and growth of lung metastases. Autophagy markers (LC3, p62, and ATF4) decreased, apoptosis increased (TUNEL, pH3/Ki-76), and the cell cycle regulator pCDC2 was inhibited. In conclusion, we here showed an anti-tumor effect of Vildagliptin via downregulation of autophagy resulting in increased apoptosis and modulation of the cell cycle. We therefore propose Vildagliptin for the evaluation as a new therapeutic approach for the treatment of colorectal cancer lung metastases.