Clusterin (CLU) is a secreted heterodimeric glycoprotein that can be produced almost ubiquitously in mammalians tissues. 1 Its gene expression is subjected to complex regulation and can change enormously according to different stimuli. 2 Cloned and identified as the most potently induced gene in the regressing rat ventral prostate following androgen-ablation, 3 CLU was almost simultaneously characterized and isolated by different research groups working in widely divergent areas. 2 CLU is coded by a single copy gene, located on chromosome 8. 4 The gene codes for an initial precursor peptide glycosylated and cleaved into two a and b chains of 40 kDa each, held together by a unique five disulfide bond motif in the extracellular mature form. 1 This secreted form of CLU has been suggested to act as a molecular chaperone following stress-induced injury, 5 clearing extracellular debris. 6 However, it has been reported the existence of an inactive, cytoplasmic form of CLU produced by alternative splicing that is converted by ionizing irradiation to a truncated mature nuclear isoform, 7 which binds the Ku70/Ku80 complex in cell-free systems8 inhibiting cell growth and survival7 probably by a caspase-3-independent mechanism. 9 Other alternative CLU isoforms, produced either by exon skipping10 or by post-translational modifications activated by apoptosis, 11, 12 were recently described. These different isoforms of CLU have been suggested to be antiapoptotic6, 13 or proapoptotic. 7, 10, 12, 14–16

These controversial reports on the role of CLU might be related to specific proteomic profiles that are produced by different apoptotic stimuli (ie the general protein pattern of CLU and the relative ratio between different CLU isoforms). This might explain why CLU has been involved in a plethora of pathophysiological processes, including cell–cell and cell–matrix adhesion, cell differentiation, transformation, aging17, 18 and cancer, 19 but its biological role still remains to be clearly established. Reports suggesting that CLU may be a potential tumor suppressor gene include the finding that CLU suppresses NF-kB activity and the metastatic phenotype of neuroblastoma cells. 20 We have previously reported that CLU overexpression inhibits cell cycle progression of simian virus 40 (SV40)-immortalized human prostate PNT2 and PNT1A epithelial cells. 21