Vitamin K2-induced cell growth inhibition via autophagy formation in cholangiocellular carcinoma cell lines.
Vitamin K2-induced cell growth inhibition via autophagy formation in cholangiocellular carcinoma cell lines.
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DOI：
10.3892/ijmm.20.6.801
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发表时间：
2007-12
影响因子：
5.4
通讯作者：
M. Enomoto;A. Tsuchida;K. Miyazawa;Tomohisa Yokoyama;Hideaki Kawakita;H. Tokita;M. Naito;M. Itoh;K. Ohyashiki;T. Aoki
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文献类型：
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作者：
M. Enomoto;A. Tsuchida;K. Miyazawa;Tomohisa Yokoyama;Hideaki Kawakita;H. Tokita;M. Naito;M. Itoh;K. Ohyashiki;T. Aoki
维生素K2（MK 4）在体外对各种类型的癌细胞系具有抗肿瘤作用，并且其功效也已报道在白血病、骨髓增生异常综合征和肝细胞癌（HCC）患者的临床应用中。然而，MK 4的抗肿瘤作用机制的细节仍不清楚。在本研究中，我们研究了MK 4对胆管细胞癌（CCC）细胞系的抗肿瘤作用及其作用机制，使用HL-60白血病细胞系，发挥MK 4诱导的细胞生长抑制，通过诱导凋亡和细胞周期阻滞作为对照。MK 4对所有三种类型的CCC细胞系都具有剂量依赖性的抗肿瘤作用。然而，凋亡发生在一个较小的百分比的细胞和有较少的细胞周期阻滞相比，其他癌细胞系研究，这表明轻微的MK 4诱导的细胞生长抑制通过凋亡诱导和细胞周期阻滞。相反，组织病理学结果显示，大量的细胞含有空泡在他们的细胞质中，和电子显微镜下的结果显示，大量的细胞质自噬体和自溶酶体。这些发现提供了自噬相关细胞死亡的证据。荧光显微镜下吖啶橙子染色显示细胞质酸性囊泡细胞器的数量增加的自噬特征。此外，在对照组中几乎没有细胞形成自噬囊泡，而在MK 4处理组中含有空泡的细胞的百分比随着培养时间的延长而增加。这些结果表明，与白血病、胃癌、HCC和其他癌细胞不同，MK 4对CCC细胞的抗肿瘤作用是通过自噬形成诱导的。
Vitamin K2 (MK4) has antitumor effects on various types of cancer cell lines in vitro, and its efficacy has also been reported in clinical applications for patients with leukemia, myelodysplastic syndrome, and hepatocellular carcinoma (HCC). However, details of the mechanism of the antitumor effects of MK4 remain unclear. In the present study, we examined the antitumor effects of MK4 on cholangiocellular carcinoma (CCC) cell lines and its mechanism of action using the HL-60 leukemia cell line that exerts MK4-induced cell growth inhibition via apoptosis induction and cell cycle arrest as a control. MK4 exerted dose-dependent antitumor effects on all three types of CCC cell lines. However, apoptosis occurred in a smaller percentage of cells and there was less cell cycle arrest compared with other cancer cell lines studied previously, which suggested slight MK4-induced cell growth inhibition via apoptosis induction and cell cycle arrest. On the contrary, histopathological fidings showed a large number of cells containing vacuoles in their cytoplasm, and electron microscopic findings showed a large number of cytoplasmic autophagosomes and autolysosomes. These findings suggested evidence of autophagy-related cell death. Fluorescence microscopy following acridine orange staining revealed an increase in the number of cytoplasmic acidic vesicular organelles characteristic of autophagy. Moreover, there were few cells forming autophagic vesicles in the control group, while the percentage of cells containing vacuoles in the MK4-treated group increased with the duration of culture. These results suggested that, unlike in leukemia, gastric cancer, HCC, and other cancer cells, the antitumor effects of MK4 on CCC cells are induced via autophagy formation.