NDRG4 sensitizes CRC cells to 5-FU by upregulating DDIT3 expression.

Abstract

The incidence of colorectal cancer (CRC) has remained high in recent years, and 5-fluorouracil (5-FU) is a vital chemotherapeutic agent for its treatment. Our previous study reported that N-myc downstream-regulated gene 4 (NDRG4) plays a tumor-suppressive role in CRC, but the mechanisms associated with NDRG4 and 5-FU chemosensitivity remain unclear. The results of the present study demonstrate that NDRG4 sensitized CRC cells to 5-FU by upregulating DNA damage inducible transcript 3 (DDIT3). NDRG4 inhibited the proliferation of CRC cells and the activation of PI3K/AKT and ERK signaling. Furthermore, NDRG4 promoted CRC cell apoptosis induced by 5-FU. Mechanistic analyses revealed that NDRG4 upregulated DDIT3 expression, and that the proapoptotic effect of NDRG4 under 5-FU treatment conditions was dependent on DDIT3. These findings support the biological value of the association between NDRG4, DDIT3 and 5-FU chemosensitivity in CRC, and may advance the clinical treatment of CRC in the future.