We report here that calcium (Ca2þ) deprivation causes translocation of a 45 kDa CLU isoform to the nucleus in human prostate epithelial cells, leading to inhibition of cell proliferation and caspase-cascade-dependent anoikis. Our data show that accumulation of nuclear CLU caused induction of apoptosis and anoikis in prostate cells, and that conditions restoring normal cell growth and survival also cause relocalization of CLU in the cytoplasm. In fact, early before induction of anoikis, we observed translocation of a 45 kDa CLU isoform in the cell nuclei that was prevented by Ca2þ or z-VAD-fmk supplementation, leading to cell rescue. Importantly, transient overexpression of an intracellular, not secreted, form of CLU accumulating into the nucleus caused cell growth inhibition and anoikis in the absence of Ca2þ deprivation. This effect was also caspase-dependent. In any condition studied, cell demise was strictly associated with translocation of CLU to the nucleus. Taken together, these data suggest that anoikis-death by Ca2þ deprivation is accompanied by nuclear translocation of a 45 kDa CLU and that a nuclear only form of CLU appears to recapitulate death by Ca2þ deprivation, suggesting a putative causative link between Ca2þ depletion, CLU nuclear translocation and cell death. CLU intracellular trafficking can now be linked to Ca2þ signalling pathway, resulting in regulation of survival and proliferation of androgen-dependent prostate epithelial cells. Moreover, the data here presented and previous results showing that CLU is downregulated during prostate cancer progression19,37 support the hypothesis that CLU is a tumorsuppressor gene for the prostate. The finding that calreticulin, an intracellular Ca2þ-binding protein, is regulated by androgens, 38 and that inhibition of spontaneous and androgeninduced prostate growth by a vitamin D analog involves CLU,39 also supports the hypothesis that a causative link between these pathways may exist. Identification of the molecular mechanisms involved in the production and processing of intra-CLU will help in the future the molecular characterization of prostate cancer, one of the most diffuse and elusive type of cancer.
Ca2+ depletion caused nuclear translocation of a 45kda death-isoform of clusterin and anoikis induction in prostate cells / A.E. CACCAMO; M. SCALTRITI; A. CAPORALI; D. D'ARCA; A. CORTI; D. CORVETTA; BETTUZZI S.. - In: CELL DEATH AND DIFFERENTIATION. - ISSN 1350-9047. - 12(2005), pp. 101-104. [10.1038/sj.cdd.4401491]