High concentrations of pyridoxal stimulate the expression of IGFBP1 in HepG2 cells through upregulation of the ERK/c-Jun pathway

Abstract

Abstract. Increasing evidence suggests that dietary vitamin B6 is linked to the prevention of cancer and cardiovascular disease. However, the molecular mechanisms involved in this process are not yet understood. Preliminary results in the current study indicated, following DNA microarray analysis and quantitative PCR, that insulin-like growth factor-binding protein 1 (IGFBP1) mRNA is upregulated in HT29 colon carcinoma cells exposed to pyridoxal (PL, 500 µM). IGFBP1 is secreted from the liver and is hypothesized to exert a protective role in the development of cancer and cardiovascular disease. Thus, further experiments were performed to investigate the effect of PL on the expression of IGFBP1 in HepG2 hepatocellular carcinoma cells. The addition of PL (500 µM) markedly increased the expression of IGFBP1 mRNA in HepG2 cells at 6, 12 and 24 h (P<0.01), whereas other vitamers (500 µM), including pyridoxal 5'-phosphate (PLP), pyridoxine (PN) and pyridoxamine (PM), caused no such effect. The expression of the IGFBP1 protein in the cell lysate and culture medium was elevated in the presence of PL. PL elevated expression of the active form of ERK1 protein, p-ERK1, and the p-c-Jun protein, a downstream factor of ERK. Furthermore, IGFBP1 expression, elevated by PL, was suppressed by PD98059, an ERK inhibitor. Higher expression of IGFBP1 protein by PL was suppressed by cycloheximide. These results suggest that PL may induce the expression of IGFBP1 in hepatoma cells via a mechanism involving the ERK/c-Jun pathway.

Targeting Resistance against the MDM2 Inhibitor RG7388 in Glioblastoma Cells by the MEK Inhibitor Trametinib

“…Furthermore, among the 20 most regulated genes in microarray analysis (Table S2) IGFBP1 (upregulated by 8-fold in RG7388 resistant cells) was the most promising candidate due to the strongest reliability of confirmation by qRT-PCR (Supplementary Fig. S6A) and immunoblot analysis (Fig 2E) as well as based on literature research demonstrating a cross-link with the ERK1/2 pathway (34,35). In addition, microarray analysis showed an activation of the p53 pathway in RG7388-resistant cells, which was also seen in GSEA ( Fig.…”

Vitamin B6 activates p53 and elevates p21 gene expression in cancer cells and the mouse colon

“…On the other hand, other B 6 -vitamers including PLP, PN and PM had no such effect on p21 mRNA expression. We recently found that PL remarkably increases IGFBP1 mRNA whereas no other B 6 -vitamers have a similar effect (11). PL can freely pass through the cell membrane, and only PL is reported to interact with the cell surface of RAW264.7 cells cultured in culture medium treated with B 6 -vitamers (i.e., PL, PM, PN and PLP) (17,18).…”

“…Accumulating evidence from in vitro and in vivo studies suggests p21 and p53 suppress cell proliferation (2,11,(19)(20)(21)(22)(23)(24)(25). In addition, p21 protects against oxidative stress (26).…”

“…We also reported that vitamin B 6 decreases oxidative stress, inflammation, cell proliferation, epithelial cell damage, and angiogenesis, which may lead to lower tumorigenesis (1,2,(7)(8)(9)(10). Moreover, we recently found that high concentrations of pyridoxal (PL) increase the expression of insulin-like growth factor-binding protein 1 (IGFBP1), a putative tumor suppressor, in human hepatoma (HepG2) cells via the upregulation of the ERK/c-Jun pathway (11). However, the molecular mechanisms involved in the antitumor effect of vitamin B 6 remain unclear.…”

A Metabolic Study on Colon Cancer Using1H Nuclear Magnetic Resonance Spectroscopy

“…It upregulates a protective factor, insulin like growth factor binding protein 1 (IGFBP1); its mRNA is upregulated in HT29 colon carcinoma cells exposed to pyridoxal (a form of vitamin B6). IGFBP1 is secreted from the liver and is hypothesized to exert a protective role in the development of cancer and cardiovascular diseases [20]. ELISA indicated analysis showed that supplemental vitamin B6 significantly lowered levels of colonic HSP70, heme-oxygenase-1, and HSP32 which increase cell proliferation and colonic damage.…”