Inhibition of phosphoserine phosphatase enhances the anticancer efficacy of 5-fluorouracil in colorectal cancer.

Most colorectal cancer (CRC) cell lines are identified to overexpress phosphoserine phosphatase (PSPH), which regulates the intracellular synthesis of serine and glycine, and supports tumor growth. In this study, the effect of PSPH on 5-fluorouracil (5-FU) efficacy was evaluated. CRC cells exposed to 5-FU acquire metabolic remodeling, resulting in increased glucose flux for PSPH-mediated serine synthesis. Then serine is converted into GSH, which promotes cell survival through the detoxification of 5-FU-induced reactive oxygen species (ROS). Consequently, repression of PSPH by the use of shRNAs for PSPH impaired the defense against drug-induced oxidative stress, thereby sensitizing cells to 5-FU. The importance of the PSPH in supporting tumor growth during 5-FU treatment was also demonstrated in an in vivo tumor model of CRC. These findings indicate that the PSPH could serve as a target for increasing the anticancer efficacy of conventional therapy in patients with CRC.