l-Mimosine blocks cell proliferation via upregulation of B-cell translocation gene 2 and N-myc downstream regulated gene 1 in prostate carcinoma cells

l-Mimosine, an iron chelator and a prolyl 4-hydroxylase inhibitor, blocks many cancer cells at the late G1 phase. B-cell translocation gene 2 ( Btg2 ) regulates the G1/S transition phases of the cell cycle. N- myc downstream regulated gene 1 ( Ndrg1 ) is a differentiation-inducing gene upregulated by hypoxia. We evaluated the molecular mechanisms of l-mimosine on cell cycle modulation in PC-3 and LNCaP prostate carcinoma cells. The effect of l-mimosine on cell proliferation of prostate carcinoma cells was determined by the [3H]thymidine incorporation and flow cytometry assays. l-Mimosine arrested the cell cycle at the G1 phase in PC-3 cells and at the S phase in LNCaP cells, thus attenuating cell proliferation. Immunoblot assays indicated that hypoxia and l-mimosine stabilized hypoxia-inducible factor-1α (HIF-1α) and induced Btg2 and Ndrg1 protein expression, but downregulated protein levels of cyclin A in both PC-3 and LNCaP cells. l-Mimosine treatment decreased cyclin D1 protein in PC-3 cells, but not in LNCaP cells. Dimethyloxalylglycine, a pan-prolyl hydroxylase inhibitor, also induced Btg2 and Ndrg1 protein expression in LNCaP cells. The transient gene expression assay revealed that l-mimosine treatment or cotransfection with HIF-1α expression vector enhanced the promoter activities of Btg2 and Ndrg1 genes. Knockdown of HIF-1α attenuated the increasing protein levels of both Btg2 and Ndrg1 by hypoxia or l-mimosine in LNCaP cells. Our results indicated that hypoxia and l-mimosine modulated Btg2 and Ndrg1 at the transcriptional level, which is dependent on HIF-1α. l-Mimosine enhanced expression of Btg2 and Ndrg1 , which attenuated cell proliferation of the PC-3 and LNCaP prostate carcinoma cells.