Ellagic acid induces cell cycle arrest and apoptosis via the TGF‑β1/Smad3 signaling pathway in human colon cancer HCT‑116 cells.

Colorectal carcinoma (CRC) is a major type of malignancy worldwide. Ellagic acid (EA), a natural phenolic constituent, has been shown to exhibit anticancer effects. In our previous study, it was shown that EA inhibited proliferation of CRC cells. Additionally, microarray analysis revealed 4,738 differentially expressed genes (DEGs) which were associated with multiple cellular events, including cell growth, apoptosis and angiogenesis. However, the associated pathways had not been validated. In the present study, it was shown that EA induced G0/G1 cell cycle arrest in HCT-116 cells, and increased apoptosis. Furthermore, DEGs identified by cDNA microarray analysis were investigated, and showed changes in five genes which were associated with the TGF-beta 1/Smad3 signaling pathway. TGF-beta 1 small interfering RNA and SIS3, a Smad3 inhibitor, were used to assess the role of TGF-beta 1 and Smad3, respectively, and it was shown that the they reduced the effects of EA on HCT-116 CRC cells. In addition, the expression patterns of downstream DEGs of the TGF-beta 1/Smad3 pathway were altered. Thus, this pathway may underlie the molecular mechanism by which EA exhibits its effects in vitro in CRC cells. Accordingly, targeting the TGF-beta 1/Smad3 pathway with anticancer agents such as EA may be potentially used to treat CRC.