Abstract
This study shows that leptin induced a rapid phosphorylation of p42/44 mitogen-activated protein kinase, an enhancement of both NF-kappaB DNA binding and transcriptional activities, and a concentration-dependent increase of HT-29 cell proliferation. These effects are consistent with the presence of leptin receptors on cell membranes. The leptin induction of cell growth was associated with an increase of cell population in S and G2/M phase compared with control cells found in G0/G1 phase of the cell cycle. Moreover, cyclin D1 immunoreactivity was enhanced in leptin-treated HT-29 cells and this increase was essentially associated with cell population in G0/G1 phase. On the other hand, we observed that sodium butyrate inhibited cell proliferation by blocking HT-29 cells in G0/G1 phase of the cell cycle. Interestingly, at physiological concentration, leptin prevented sodium butyrate-induced morphological nucleus changes, DNA laddering and suppressed butyrate-induced cell cycle arrest. This anti-apoptotic effect of leptin was associated with HT-29 cell proliferation and activation NF-kappaB pathways. However, the phosphorylation of p42/44 MAP kinase in response to leptin was reduced in butyrate-treated cells. These data demonstrated that leptin is a potent mitogenic factor for intestinal epithelial cells through the MAP kinase and NF-kappaB pathways. They also showed, for the first time, that leptin promotes colon cancer HT-29 cell survival upon butyrate challenge by counteracting the apoptotic programs initiated by this short chain fatty acid probably through the NF-kappaB pathways. Although further studies are required to unravel the precise mechanism, these data may have significance in the pathogenesis of colorectal cancer and ulcerative colitis diseases.
Highlights
This study shows that leptin induced a rapid phosphorylation of p42/44 mitogen-activated protein kinase, an enhancement of both NF-B DNA binding and transcriptional activities, and a concentration-dependent increase of HT-29 cell proliferation
Cyclin D1 immunoreactivity was enhanced in leptin-treated HT-29 cells and this increase was essentially associated with cell population in G0/G1 phase
We have demonstrated that human colonic HT-29 cells expressing the leptin receptor can sense and respond to physiological concentration of leptin by increasing their proliferation
Summary
Ob-R, leptin receptor; MAP, mitogenactivated protein; HT-29, human colon cancer cells, NF-B, nuclear factor B transcription factor; PI, propidium iodide; ERK, extracellular signal-regulated kinase; PBS, phosphate-buffered saline; NaB, sodium butyrate; FITC, fluorescein isothiocyanate; TRITC, tetramethylrhodamine isothiocyanate; ELISA, enzyme-linked immunosorbent assay; EMSA, electrophoretic mobility shift assay. Challenge by counteracting the apoptotic programs initiated by this short chain fatty acid, probably through activation of NF-B pathways
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