| BACKROUND: Sirolimus is a mammalian target of rapamycin (mTOR) speci- ficity inhibitory. Sirolimus can significantly inhibit the growth of tumors, but its mechanisms are not very clear. We investigate the inhibitory effects of sirolimus on cell proliferation and the expression of mTOR, HIF-1αand VEGF in human pancreatic carcionoma SW1990 cells, and discuss the potential signaling pathway mechanism of selective mTOR inhibitor- sirolimus effect on pancreatic carcinoma cell line.METHODS: The human pancreatic carcinoma SW1990 cells were incubated under hypoxic condition. Different concentration of sirolimus (0.01nmol/L-100000 nmol/L) were applied in cells in vitro for 24 hours. MTT method was used to investigate the effects on cell proliferation. The effects of different dose of sirolimus on the mRNA expression of mTOR, HIF-1αand VEGF were determined by semi-quantitative RT-PCR in SW1990 cells. Changes in the expression of mTOR, HIF-1αand VEGF protein at different concentration of sirolimus were determined by Western Blot.RESULTS: Sirolimus could significantly inhibit the proliferation of human pancreatic carcinoma SW1990 cells. The inhibition ratio induce by sirolimus were found to increase gradually with the increasing of the dose. The mRNA level of mTOR and VEGF in sirolimus-treat cells decreased (P<0.05), compared with those in untreated controls with a concentration-independent manner. The mRNA expression level of HIF-1αwas unchanged although treated with different concentration of sirolimus. Also sirolimus could effectively inhibit the protein level of mTOR, HIF-1αand VEGF, which demanstrat the highest inhibitory effect in the highest concentration group.CONCLUSION: Sirolimus could down-regulate the VEGF transcription mediated by HIF-1αat hypoxia condition in vitro, which is independent on mTOR signaling transduction pathway in pancreatic carcinoma SW1990 cells. These mechanisms may induce apoptosis in SW1990 cell line and relate to anticancer function of sirolimus. |
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