Presentation Authors: Yoichi Osako*, Hirofumi Yoshino, Masaya Yonemori, Shuichi Tatarano, Hideki Enokida, Masayuki Nakagawa, Kagoshima, Japan
Introduction: According to data from SEER (http://seer.cancer.gov/) in the United States, bladder cancer (BC) has improved 5-year survival rate by only 3% in the last two decades. D - 3 - phosphoglycerate dehydrogenase (PHGDH) is an enzyme that converts 3 - phosphoglycerate on glycolysis system and induces metabolism to serine synthesis. Cancers require serine to maintain rapid, sustained and uncontrollable proliferation. Recently it has been reported that PHGDH can be a therapeutic target in breast cancer and melanoma, on the other hand there has been no report on BC. The aim of this study is to evaluate therapeutic possibility regarding PHGDH in BC.
Methods: Clinical significance of PHGDH in BC was analyzed using The Cancer Genome Atlas (TCGA) which is a public database. In addition, the effect of PHGDH inhibitor (NCT-503) and si-RNA against PHGDH was evaluated by cell proliferation and apoptosis assay in BC cell lines (T24, BOY, KK47, UMUC-3, J82). In xenograft assay, PHGDH knockdown efficiency was investigated using sh-RNA against PHGDH. Furthermore, additive effect of the PHGDH inhibitor under Gemcitabine and Cisplatin (GC) administration was examined.
Results: In the PHGDH high expression group (n = 157), the prognosis was poor (P = 0.0032) compared with the low expression group (n = 247), and PHGDH was found to be an independent poor prognostic factor (P = 0.001) in multivariate analysis. The PHGDH inhibitor and PHGDH si-RNAs significantly inhibited proliferative ability through induction of apoptosis (P < 0.05) in BC cell lines. Western blot analyses showed that Ki-67 expression was markedly repressed and cleaved caspase-3 expression was increased in PHGDH knockdown BC cells compared with those in control BC cells. Additionally, cells with PHGDH overexpression promoted tumor cell viability in comparison to control cells. In xenograft assay, PHGDH knockdown by sh-RNA significantly inhibited tumor progression compared to the vehicle group (P < 0.05). Furthermore, the combination treatment between PHGDH inhibitor and GC showed synergistic tumor suppressive effect compared to each single agent group (P < 0.05) in proliferation assay.
Conclusions: Our study revealed that PHGDH inhibition showed tumor suppressive effects in BC. Furthermore, the combination therapy between PHGDH inhibitor and GC showed synergistic effect in proliferation assay. Novel therapeutic implications through functional analysis of PHGDH in BC were suggested.