Stable expression of C/EBPα in prostate cancer cells down‐regulates metallothionein and increases zinc‐induced toxicity

BACKGROUND: The transcription factor C/EBPalpha regulates terminal differentiation of various cell types. C/EBPalpha is expressed in prostate epithelium but its role in prostate development and malignant transformation is unknown. In examining the effect of forced expression of C/EBPalpha on the global gene expression profile in prostate cancer cells, we found that C/EBPalpha significantly decreased the RNA level of metallothioneins (MTs). METHODS: The prostate cancer cell lines DU145, LNCaP, and PC3 with stable overexpression of C/EBPalpha were established with a retroviral expression system. MT expression was assayed by Western blot analysis and with the MT promoter in a plasmid using luciferase as a reporter. RESULTS: Under basal conditions and in response to zinc, forced overexpression of C/EBPalpha decreased expression of MT isoforms 1A, B, F, and H, IIA and III. Following zinc exposure C/EBPalpha inhibited MT promoter activity by 1.5-2.5-fold. Overexpression of C/EBPalpha led to increased cytotoxicity of zinc at concentration of 150 microM in DU145 and LNCaP cells. CONCLUSIONS: Our data demonstrated that expression of MTs in prostate cancer cells is inhibited by C/EBPalpha and the effect may have functional significance in regulating the growth of prostate cancer cells and the response of these cells to environment stresses.