Furthermore we demonstrated that the prognosis
Furthermore, we demonstrated that the prognosis was poor for GC patients with a high KIF14 gamma-Glu-Cys (P < 0.01). These findings suggest that KIF14 is a promising target for GC therapy, although it requires further verification. To date, many of the reported kinesin inhibitors have been tested, but not against KIF14 [52,53]. It is possible that some existing molecules already target this protein. The progression of other mitotic kinesin inhibitors into clinical trials and the fact that the motor domain is selectively targetable with inhibitors also offer promise for KIF14 as a potential therapeutic target.
Although the exact mechanism of how KIF14 is involved in the tumorigenesis of GC remains to be clarified, our GSEA analysis showed that a higher expression of KIF14 was associated with proliferation, metastasis and EMT pathways. These pathways all contribute to the tumorigenesis of GC , and the bioinformatics analyses were in agreement with the aforementioned in vitro and in vivo results. Moreover, we showed that Akt phosphorylation was inhibited by KIF14 downregulation, which suggested a significant role for KIF14 in the activation of the Akt in GC. By using the Akt inhibitor MK‑2206 and Akt re-expression, we demonstrated that the activation of p‑Akt was involved in KIF14 stimulated cell growth and metastasis, but the underlying mechanism still needs a deeper exploration.
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Acknowledgements This work was supported by National Natural Science Foundation of China No. 81772518, 81201915, 81772509, 91529302; Multicenter Clinical Trial of Shanghai Jiao Tong University School of Medicine NO. DLY201602; and Foundation for Shanghai Jiao Tong University School of Medicine NO. 13XJ10011. And we would like to thank the Genminix Informatics Ltd., Co. for assisting us with data analysis.
Introduction Pyridoxal 5′-phosphate (PLP), the co-enzymatically active form of vitamin B6, is one of the most versatile cofactors found in nature. In mammals, PLP-dependent enzymes catalyze ~140 different types of biochemical transformations, including reactions that are required for neurotransmitter-, amino acid- and glycogen metabolism . PLP is a highly reactive aldehyde that transiently forms a Schiff base with the ε-amino group of the active site lysine in its cognate apo-enzymes . It is thought that intracellular PLP concentrations and PLP trafficking are tightly controlled to ensure sufficient PLP supply to apo-enzymes, while minimizing free PLP levels. This is important to prevent non-specific reactions of PLP with cellular nucleophiles and proteins that are not B6 enzymes [, , ]. Intracellular PLP levels depend on the availability and -transport of PLP precursors , the biosynthetic activities of pyridoxal 5′-kinase (PDXK) and pyridox(am)ine 5′-phosphate oxidase (PNPO), the extent of PLP scavenging by proteins and small molecules, PLP binding to carriers such as PROSC, PDXK and PNPO, and PLP hydrolysis by pyridoxal 5′-phosphate phosphatase (PDXP) [3,4,7]. Specifically, PDXK catalyzes the phosphorylation of pyridoxine (PN), pyridoxamine (PM) or pyridoxal (PL) to their 5′-phosphorylated variants PNP, PMP or PLP. PNPO additionally (re)generates PLP from PNP or PMP by catalyzing the oxidation of their respective hydroxyl or amino groups to the co-enzymatically essential aldehyde moiety of PLP  (Fig. 1). The pathways of PLP biosynthesis have been established for decades, yet a dedicated PLP phosphatase (PDXP) was cloned more recently . PDXP activity may play a significant role in the regulation of cellular PLP concentrations [7,8]. Nonetheless, the relative importance of PDXP for the regulation of PLP homeostasis and for PLP-dependent functions in vivo is unknown.