Pyridoxine 5\u2032-phosphate oxidase is a novel therapeutic target and regulated by the TGF-\u03b2 signalling pathway in epithelial ovarian cancer

Lingyun Zhang,Wencai Guan,Yulong Ye,Qunbo Lin,Tiankui Qiao,Yaning Zhang,Guoxiong Xu,Yun Wu,Jimin Shi,Xulei Zuo,Daibing Zhou,Kristin L Connor,Jinguo Zhang,Wenwen Sun,Weimin Ren

doi:10.1038/s41419-017-0050-3

Abstract

Pyridoxine 5′-phosphate oxidase (PNPO) is an enzyme that converts pyridoxine 5′-phosphate into pyridoxal 5′-phosphate (PLP), an active form of vitamin B6 implicated in several types of cancer. However, the role of PNPO and its regulatory mechanism in epithelial ovarian cancer (EOC) are unknown. In the present study, PNPO expression in human ovarian tumour tissue and its association with the clinicopathological features of patients with EOC were examined. Further, the biological function of PNPO in EOC cells and in xenograft was evaluated. We demonstrated for the first time that PNPO was overexpressed in human EOC. Knockdown of PNPO induced EOC cell apoptosis, arrested cell cycle at G2/M phase, decreased cell proliferation, migration and invasion. Xenografts of PNPO-shRNA-expressing cells into the nude mouse attenuated tumour growth. PNPO at mRNA and protein levels in EOC cells was decreased after transforming growth factor-β1 (TGF-β1) treatment. The inhibitory effect of TGF-β1 on PNPO expression was abolished in the presence of SB-431542, a TGF-β type I receptor kinase inhibitor. Moreover, we found that TGF-β1-mediated PNPO expression was at least in part through the upregulation of miR-143-3p. These data indicate a mechanism underlying PNPO regulation by the TGF-β signalling pathway. Furthermore, PLP administration reduced PNPO expression and decreased EOC cell proliferation, suggesting a feedback loop between PLP and PNPO. Thus, our findings reveal that PNPO can serve as a novel tissue biomarker of EOC and may be a potential target for therapeutic intervention.

Highlights

Human ovarian cancer (OC) is the most deadly disease in women
We evaluated the association between Pyridoxine 5′-phosphate oxidase (PNPO) protein expression and the clinical characteristics of patients with OC using tissue microarray (Fig. 1b and Supplementary Table S1)
By analysis of histological types, we found that PNPO protein expression was significantly associated with surface epithelial malignant tumours compared with sex cord-stromal and germ cell tumours (P < 0.001, Fig. 1b)

Summary

Introduction

Human ovarian cancer (OC) is the most deadly disease in women. There are three main types of cancer: epithelial, sex cord-stromal and germ cell tumours[1,2,3]. Epithelial ovarian cancer (EOC), derived from the epithelial cells of the ovary or the fallopian tube[4], accounts for more than 90% of total OC and occurs most commonly in postmenopausal women[5]. Vitamin B6 exist as six vitamers, including pyridoxine (PN), pyridoxamine (PM), pyridoxine 5′-phosphate (PNP), pyridoxamine 5′-phosphate (PMP), pyridoxal 5′-phosphate (PLP) and pyridoxal (PL)[8]. Dietary PN and PM serve as the main source of PNP and PMP. Oxidation of PNP and PMP produces PLP which can be further metabolized to PL through enzymatic hydrolysis[9,10]. PLP, an active form of vitamin B6, is an essential cofactor required by many enzymes for metabolic processes

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Conclusion