<p>ODC1 promotes proliferation and mobility via the AKT/GSK3β/β-catenin pathway and modulation of acidotic microenvironment in human hepatocellular carcinoma</p>

Abstract

Purpose: Ornithine decarboxylase 1 (ODC1)-an oncogene involved in the biosynthesis of polyamines-is commonly upregulated and associated with poor prognosis in numerous cancers. However, the role and mechanism of ODC1 in hepatocellular carcinoma (HCC) remains unclear. The aim of the present study was to investigate the role of ODC1 in HCC and clarify the latent molecular mechanisms. Material and methods: We used samples obtained from The Cancer Genome Atlas. The expression of ODC1 was also assessed in our additional HCC samples and HCC cell lines. The roles of ODC1 in HCC cell proliferation, migration and invasion in vitro were investigated using the cell-counting kit-8 assay, 5-ethynyl-2´-deoxyuridine assay, colony formation assay, flow cytometry, wound healing assay and transwell assay, respectively. The effect of ODC1 on HCC cell proliferation in vivo was investigated by constructing a xenotransplanted tumor model in nude mice. Quantitative real-time polymerase chain and western blotting were used to detect the expression levels of ODC1 in mimetic hypoxia, nutrient depleted, and acidotic microenvironment. The relationships between ODC1, the AKT/GSK3β/β-catenin pathway, and acidotic microenvironment were further investigated through western blotting, immunohistochemical staining, and immunofluorescence. Results: ODC1 was upregulated in HCC tissues and cell lines, and co-expressed with KI67 and PCNA (P<0.05). A decrease in the expression of ODC1 inhibits proliferation, migration, invasion, and induces cell cycle arrest in HCC cell lines in vitro, while suppressing HCC cell proliferation in vivo (P<0.05). Furthermore, the expression of ODC1 was increased in the mimetic acidotic microenvironment, while the interference with the expression of ODC1 reversed the effect of the acidotic microenvironment through regulation of AKT/GSK3β/βcatenin and related downstream proteins. Conclusion: ODC1 is an unfavorable gene in HCC patients,promoting HCC cell proliferation, migration and invasion via the AKT/GSK3β/β-catenin pathway and modulation of the acidotic microenvironment.

<p>Simultaneous Inhibition of Ornithine Decarboxylase 1 and Pyruvate Kinase M2 Exerts Synergistic Effects Against Hepatocellular Carcinoma Cells</p>

“…Previous studies have shown that both ODC1 and PKM2 regulate the AKT/GSK-3β/β-catenin pathway and promote the development of various cancers. 18,22 Therefore, we determined whether DFMO and compound 3k exert synergistic effects on HCC cells via the AKT/GSK-3β/ β-catenin pathway. The Western blotting results showed that the combination treatment significantly decreased the expression of p-AKT (Ser473), p-GSK-3β (Ser9), and β-catenin in HepG2 and SMMC-7721 cells compared to single drugs and DMSO treatment ( Figure 7A, P<0.05).…”

“…17 Our previous study showed that an acidic microenvironment (simulated by lactate) promoted proliferation and migration of HCC cells by increasing ODC1 expression. 18 In the current study, we aimed to reveal the relationship between the key lactate metabolism enzyme PKM2 and the polyamine metabolism enzyme ODC1, and to determine whether simultaneous inhibition of ODC1 and PKM2 by DFMO and compound 3k, respectively, exerts synergistic effects against HCC cells. The results suggested that this approach may represent a novel treatment for HCC.…”

Elucidating evolutionarily conserved mechanisms of diapause regulation using an in silico approach

“…Thus, prolactin signaling can end diapause via inhibition of FOXO3 as well as through synthesis of polyamines. In addition to other numerous roles, polyamines can also upregulate AKT1 [46,47], which in turn downregulates FOXO3 to allow proliferation. Hence, we propose that prolactin signaling can inhibit FOXO3 either directly or indirectly through polyamines in diapause species and signal the re-emergence of embryo from diapause by resuming cell growth and development.…”

Magnetic fields, cancer and circadian rhythms: hypotheses on the relevance of intermittence and cycling

“…100% change of activity). It is noteworthy that ODC is a possible target in oncology, because it contributes to polyamine-induced cell proliferation and it is often overexpressed in breast, prostate, colorectal and endometrial cancers [19].…”