Gastric cancer (GC) is one of the most common malignancies in the world. Fluorouracil (5-FU) is widely used in the treatment of cancers, but resistance to 5-FU results in the failure of chemotherapy. Phosphoglycerate dehydrogenase (PHGDH) has been reported to play a vital role in the development of 5-FU resistance in cancer cells. However, the exact role of PHGDH and the underlying mechanisms for 5-FU resistance in GC cells remain elusive. In this study, PHGDH expression was much higher in the GC tissues of 5-FU-resistant patients than that in the GC tissues of 5-FU-sensitive patients. Moreover, the expression of PHGDH was obviously increased in BGC823/5-FU cells compared with that in BGC823 cells. 5-FU treatment significantly reduced the viability of BGC823/5-FU cells, in a dose- and time-dependent manner. Furthermore, 5-FU treatment inhibited the proliferation of BGC823/5-FU cells, as evidenced by decreased cell viability and reduced colony-forming ability. The knockdown of PHGDH made possible the inhibitory effect of 5-FU on the proliferation of BGC823/5-FU cells. Furthermore, 5-FU treatment promoted apoptosis of BGC823/5-FU cells, as indicated by increased numbers of TUNEL-positive cells and increased rates of apoptosis. Notably, the promoting effect of 5-FU on the apoptosis of BGC823/5-FU cells was markedly enhanced by PHGDH knockdown. Additionally, 5-FU treatment downregulated Bcl-2 expression and upregulated the expression of Bax and caspase-3, and this effect was remarkably enhanced by PHGDH knockdown. In conclusion, knockdown of PHGDH potentiates 5-FU cytotoxicity in GC cells via the Bcl-2/Bax/caspase-3 signaling pathway.
Keywords: Phosphoglycerate dehydrogenase; cytotoxicity; fluorouracil; gastric cancer.
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