The glutamyl-prolyl-tRNA synthetase 1 inhibitor halofuginone exerts synergistic antitumor effects with bortezomib in colon cancer cells.

Glutamyl-prolyl-tRNA synthetase 1 (EPRS1) is a key enzyme in protein synthesis and is implicated in various diseases, including inflammation, fibrosis, and cancer. Here, we found that EPRS1 is highly expressed in patients with colon cancer and is positively correlated with poor prognosis. Halofuginone, a derivative of febrifugine extracted from the traditional Chinese herb Dichroa febrifuga, was previously identified as a specific inhibitor of EPRS1. Our research found that halofuginone significantly inhibit the growth of colon cancer cells. Mechanistic investigations demonstrated that halofuginone treatment activates the ATF4-CHOP and JNK signaling pathways in colon cancer cells. Further research revealed that halofuginone inhibits the expression of NRF2, and that high NRF2 expression can reverse halofuginone's anti-colon cancer activity. Importantly, the inhibition of NRF2, along with the activation of the ATF4-CHOP and JNK signaling pathways caused by halofuginone, can be substantially reversed by proline. Additionally, we observed a synergistic antitumor effect when halofuginone was combined with bortezomib, a well-established proteasome inhibitor, in colon cancer cells. These results imply that the halofuginone-bortezomib combination could offer a promising therapeutic option for colon cancer treatment. In summary, our research comprehensively elucidates the molecular mechanisms underlying halofuginone's action against colon cancer and provides new insights into halofuginone-based combination therapies.