Loss of caspase-1 and caspase-3 protein expression in human prostate cancer

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 apopt osis in response to transforming growth factor-beta (Y. Guo and N, Kypriano u, Cancer Res., 59: 1366-1371, 1999), In the present study, to identify the significance of caspases in prostate cancer progression, we examined the e xpression of three key caspases, caspase-1, caspase-3, and caspase-9, in no rmal and malignant human prostates. Caspase-1, -3, and -9 expression was ex amined at the mRNA and the protein level in a series of human normal and ma lignant prostate specimens. No significant differences were observed in the mRNA expression in prostatic tumors relative to the normal gland for any o f the three caspases, Immunohistochemical analysis revealed that the patter n of protein expression and distribution was uniformly homogeneous in the n ormal prostate, with the epithelial cells exhibiting a diffuse cytoplasmic staining for caspase-1 and caspase-3. Significantly, the majority of primar y prostate cancer specimens (80%) had total lack of caspase-1 immunoreactiv ity, whereas the remaining showed a significantly reduced expression compar ed with the normal prostate (P < 0.05). Caspase-3 expression was also reduc ed in moderately and poorly differentiated prostatic tumors compared with w ell-differentiated prostate adenocarcinomas and the normal prostate (P < 0. 05). No significant correlation was found between the apoptotic index or Gl eason grade and the pattern of caspase protein expression in the primary pr ostatic tumors analyzed. Western blot analysis revealed constitutive expres sion 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 expressio n was low in the less tumorigenic cell lines, DU-145 and LNCaP, These findi ngs implicate the loss of caspase-1 protein as a potential step in the loss of apoptotic control during prostate tumorigenesis. This study suggests th at the pattern of caspase-1 and -3 expression in prostatic tumors may have prognostic significance in disease progression.