Abstract
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.
Highlights
Accumulating evidence has revealed that a minor population of tumor cells, called cancer stem cells or tumor-initiating cells (TICs), organizes a cellular hierarchy in a similar fashion to normal stem cells and shows pronounced tumorigenic activity in xenograft transplantations [1]
The percentage of apoptotic cells was roughly ten-fold higher among hepatocellular carcinoma (HCC) cells treated with DSF (1 mM) than among control cells (Figure S1C)
These results indicate that DSF reduced the tumorigenicity of HCC cells
Summary
Accumulating evidence has revealed that a minor population of tumor cells, called cancer stem cells or tumor-initiating cells (TICs), organizes a cellular hierarchy in a similar fashion to normal stem cells and shows pronounced tumorigenic activity in xenograft transplantations [1]. Besides the identification of tumor-initiating HCC cells, cancer-related molecules and signaling pathways, such as the polycomb group proteins, NANOG, AKT/ PKB signal, and Wnt/b-catenin, have been shown to play an important role in maintaining or augmenting of tumor-initiating capability of TICs [4]. Inhibitors of these molecules and signaling pathways may be potent TIC-targeting drugs, no effective therapy targeting TICs has been developed. Recent reports showed that DSF reduced the number of tumorinitiating cells and attenuated their sphere-forming abilities in breast cancer and glioblastoma [6,7]. These findings indicate that DSF could eradicate TICs, the molecular machinery of its effect against TICs still remains largely unknown
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