Activation of the caspase cascade is involved in the execution of apoptosis in a variety of cellular systems. Recent studies demonstrated that caspase-1 activation was required for human prostate cancer cells to undergo apoptosis in response to transforming growth factor-beta (Y. Guo and N. Kyprianou, Cancer Res., 59: 1366-1371, 1999). In the present study, to identify the significance of caspases in prostate cancer progression, we examined the expression of three key caspases, caspase-1, caspase-3, and caspase-9, in normal and malignant human prostates. Caspase-1, -3, and -9 expression was examined at the mRNA and the protein level in a series of human normal and malignant prostate specimens. No significant differences were observed in the mRNA expression in prostatic tumors relative to the normal gland for any of the three caspases. Immunohistochemical analysis revealed that the pattern of protein expression and distribution was uniformly homogeneous in the normal prostate, with the epithelial cells exhibiting a diffuse cytoplasmic staining for caspase-1 and caspase-3. Significantly, the majority of primary prostate cancer specimens (80%) had total lack of caspase-1 immunoreactivity, whereas the remaining showed a significantly reduced expression compared with the normal prostate (P < 0.05). Caspase-3 expression was also reduced in moderately and poorly differentiated prostatic tumors compared with well-differentiated prostate adenocarcinomas and the normal prostate (P < 0.05). No significant correlation was found between the apoptotic index or Gleason grade and the pattern of caspase protein expression in the primary prostatic tumors analyzed. Western blot analysis revealed constitutive expression of the proenzyme forms of caspase-1, -3, and -9 in the human prostate cancer cell lines PC-3, DU-145, TSU-Pr1m and LNCaP, but caspase-1 expression was low in the less tumorigenic cell lines, DU-145 and LNCaP. These findings implicate the loss of caspase-1 protein as a potential step in the loss of apoptotic control during prostate tumorigenesis. This study suggests that the pattern of caspase-1 and -3 expression in prostatic tumors may have prognostic significance in disease progression.