Disulfiram Eradicates Tumor-Initiating Hepatocellular Carcinoma Cells in ROS-p38 MAPK Pathway-Dependent and -Independent Manners

作者：Chiba Tetsuhiro^*; Suzuki Eiichiro; Yuki Kaori; Zen Yoh; Oshima Motohiko; Miyagi Satoru; Saraya Atsunori; Koide Shuhei; Motoyama Tenyu; Ogasawara Sadahisa; Ooka Yoshihiko; Tawada Akinobu; Nakatsura Tetsuya; Hayashi Takehiro; Yamashita Taro; Kaneko Syuichi; Miyazaki Masaru; Iwama Atsushi; Yokosuka Osamu

来源：PLos One, 2014, 9(1): e84807.

DOI：10.1371/journal.pone.0084807

Tumor-initiating cells (TICs) play a central role in tumor development, metastasis, and recurrence. In the present study, we investigated the effect of disulfiram (DSF), an inhibitor of aldehyde dehydrogenase, toward tumor-initiating hepatocellular carcinoma (HCC) cells. DSF treatment suppressed the anchorage-independent sphere formation of both HCC cells. Flow cytometric analyses showed that DSF but not 5-fluorouracil (5-FU) drastically reduces the number of tumor-initiating HCC cells. The sphere formation assays of epithelial cell adhesion molecule (EpCAM)(+) HCC cells co-treated with p38-specific inhibitor revealed that DSF suppresses self-renewal capability mainly through the activation of reactive oxygen species (ROS)-p38 MAPK pathway. Microarray experiments also revealed the enrichment of the gene set involved in p38 MAPK signaling in EpCAM(+) cells treated with DSF but not 5-FU. In addition, DSF appeared to downregulate Glypican 3 (GPC3) in a manner independent of ROS-p38 MAPK pathway. GPC3 was co-expressed with EpCAM in HCC cell lines and primary HCC cells and GPC3-knockdown reduced the number of EpCAM(+) cells by compromising their self-renewal capability and inducing the apoptosis. These results indicate that DSF impaired the tumorigenicity of tumor-initiating HCC cells through activation of ROS-p38 pathway and in part through the downregulation of GPC3. DSF might be a promising therapeutic agent for the eradication of tumor-initiating HCC cells.

• 出版日期2014-1-13