Repression of phosphoglycerate dehydrogenase sensitizes triple-negative breast cancer to doxorubicin.

Abstract

Approximately 70% of triple-negative breast cancer (TNBC) cell lines are identified to upregulate phosphoglycerate dehydrogenase (PHGDH), which regulates the intracellular synthesis of serine and glycine, and promotes tumor growth. In this work, the impact of this pathway on doxorubicin efficacy was evaluated. MDA-MB-468, BT-20 and HCC70 cells were transfected with lentiviral vectors expressing short hairpin RNA (shRNA) against PHGDH. In response to doxorubicin treatment, cellular proliferation was measured, ROS were evaluated and intracellular levels of serine, glycine and glutathione (GSH) were determined using liquid chromatography-mass spectrometry. A TNBC orthotopic tumor model was used to examine the effect of PHGDH on doxorubicin efficacy in vivo. TNBC cells exposed to doxorubicin undergo metabolic remodeling, resulting in increased glucose flux for serine synthesis regulated by PHGDH. Serine is then converted into GSH, which counters doxorubicin-induced formation of ROS. Consequently, suppression of PHGDH by the use of the shRNA caused doxorubicin-induced oxidative stress and increased doxorubicin sensitivity. The enhancement of doxorubicin efficacy through simultaneous suppression of PHGDH was validated in a mouse tumor model. These results shed light on PHGDH that could be a promising target for increasing the effectiveness of chemotherapy in patients with TNBC.