Ursolic acid promotes colorectal cancer cell apoptosis and inhibits cell proliferation via modulation of multiple signaling pathways

Abstract

The development of colorectal cancer (CRC) is strongly correlated with the aberrant activation of multiple intracellular signaling transduction cascades including STAT3, ERK, JNK and p38 pathways which usually function redundantly. In addition, crosstalk between these pathways forms a complicated signaling network that is regulated by compensatory mechanisms. Therefore, most of the currently used and single-target-based antitumor agents might not always be therapeutically effective. Moreover, long-term use of these agents often generates drug resistance. These problems highlight the urgent need for the development of novel anticancer chemotherapies. Ursolic acid (UA) is a major active compound present in many medicinal herbs that have long been used for the clinical treatment of CRC. Although previous studies have demonstrated an antitumor effect for UA, the precise mechanisms of its tumoricidal activity are not well understood. In the present study, using CRC mouse xenograft model and the HT-29 human colon carcinoma cell line, we evaluated the efficacy of UA against tumor growth in vivo and in vitro and investigated the underlying molecular mechanisms. We found that UA inhibits cancer growth without apparent toxicity. Furthermore, UA significantly suppresses the activation of several CRC-related signaling pathways and alters the expression of critical target genes. These molecular effects lead to the induction of apoptosis and inhibition of cellular proliferation. These data demonstrate that UA possesses a broad range of anticancer activities due to its ability to affect multiple intracellular targets, suggesting that UA could be a novel multipotent therapeutic agent for cancer treatment.