Metallothioneins and resistance to cisplatin and radiation in prostate cancer.

OBJECTIVES: The metallothioneins (MTs) are a family of small molecular weight trace metal and free radical scavenging proteins well established to play a role in the resistance to chemotherapy and radiotherapy in human cancers. MT gene expression is upregulated in response to the presence of metal ions such as zinc. Because prostatic tissue has the greatest concentration of zinc in the human body, in this study we analyzed the effect of MT induction by zinc in prostate cancer (PCa). METHODS: The activation of MT gene expression in response to zinc treatment in LNCaP and C4-2 PCa cells was shown by Western blotting and DNA microarray analysis. Chemotherapy and radiation sensitivity assays of cells after treatment with cisplatin or radiation were performed in the presence, or absence, of 150 microM ZnSO4, and cell viability was measured after 72 hours by MTS viability and clonogenic and flow cytometry assays. The experiments were repeated three times and the data analyzed. RESULTS: Increasing concentrations of ZnSO4 upregulated MT expression in a dose-dependent manner. Microarray analysis demonstrated a specific increase in MT expression. Cells treated with zinc demonstrated a significantly decreased sensitivity to cisplatin and radiotherapy compared with controls (P <0.05). CONCLUSIONS: Our data have confirmed that treatment of PCa with zinc causes an increase in MT expression, which is significantly associated with resistance to cisplatin chemotherapy and radiotherapy in PCa. Therapeutic targeting of MT may therefore provide a means to overcome resistance to radiotherapy and cisplatin chemotherapy in PCa.