Abstract
BackgroundGlucose-6-phosphate dehydrogenase (G6PD), elevated in tumor cells, catalyzes the first reaction in the pentose-phosphate pathway. The regulation mechanism of G6PD and pathological change in human melanoma growth remains unknown.MethodsHEM (human epidermal melanocyte) cells and human melanoma cells with the wild-type G6PD gene (A375-WT), G6PD deficiency (A375-G6PD∆), G6PD cDNA overexpression (A375-G6PD∆-G6PD-WT), and mutant G6PD cDNA (A375-G6PD∆-G6PD-G487A) were subcutaneously injected into 5 groups of nude mice. Expressions of G6PD, STAT3, STAT5, cell cycle-related proteins, and apoptotic proteins as well as mechanistic exploration of STAT3/STAT5 were determined by quantitative real-time PCR (qRT-PCR), immunohistochemistry and western blot.ResultsDelayed formation and slowed growth were apparent in A375-G6PD∆ cells, compared to A375-WT cells. Significantly decreased G6PD expression and activity were observed in tumor tissues induced by A375-G6PD∆, along with down-regulated cell cycle proteins cyclin D1, cyclin E, p53, and S100A4. Apoptosis-inhibited factors Bcl-2 and Bcl-xl were up-regulated; however, apoptosis factor Fas was down-regulated, compared to A375-WT cells. Moderate protein expressions were observed in A375-G6PD∆-G6PD-WT and A375-G6PD∆-G6PD-G487A cells.ConclusionsG6PD may regulate apoptosis and expression of cell cycle-related proteins through phosphorylation of transcription factors STAT3 and STAT5, thus mediating formation and growth of human melanoma cells. Further study will, however, be required to determine potential clinical applications.
Highlights
Glucose-6-phosphate dehydrogenase (G6PD), elevated in tumor cells, catalyzes the first reaction in the pentose-phosphate pathway
The expression of G6PD mRNA, protein quantity, and G6PD activity were all higher in A375 cells than those in normal human epidermal melanocytes (HEM) cells
Effect of G6PD deficiency on tumor formation in nude mice injected with A375 cell lines Tumor formation was observed in 2 of 5 mice injected with A375-G6PDΔ cells
Summary
Glucose-6-phosphate dehydrogenase (G6PD), elevated in tumor cells, catalyzes the first reaction in the pentose-phosphate pathway. G6PD abnormalities affect as much as 7.5% of the global population, with a wide range of occurrence based on geographic distribution G6PD Mahidol is a common deficient variant caused by a (163)glycine-serine mutation that occurs in about 15% of individuals in populations across Southeast Asia [7,8]. The prevalence of this mutation can be accounted for by strong positive selection over the past 1500 years that occurred in response to certain parasites, including malaria-causing agents such as Plasmodium vivax and Plasmodium falciparum, that target humans [9]. While G6PD Mahidol may confer a selective advantage to parasitic infections, such as malaria, this genetic variation may have other detrimental affects to the immune response and may be implicated in the cell cycle of abnormal or cancerous cells [9,10]
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