Clusterin Isoforms Differentially Affect Growth and Motility of Prostate Cells: Possible Implications in Prostate Tumorigenesis

Abstract

Besides a fully processed, secreted form of clusterin (sCLU), an alternative proapoptotic form of the protein targeting the nucleus (nCLU) was recently described. The possible differential roles played by the two clusterin forms in growth and motility of nonmalignant and malignant prostate cells are investigated here. sCLU or nCLU was transiently transfected in both androgen-independent prostate cancer cells (PC3 and DU 145) and immortalized prostate epithelial cells (PNT1A, a nontumoral control). Then, cell growth, motility, and cytoskeleton organization were studied. We found that (a) in PNT1A cells, both sCLU and nCLU significantly decreased cell proliferation and motility; (b) in PC3 and DU 145 cancer cells, only nCLU inhibited cell growth and migration, with sCLU being ineffective; and (c) the antimotility effect of nCLU was accompanied by a dramatic dismantling of the actin cytoskeleton. Moreover, transfection with ''full-length'' CLU cDNA produced both sCLU and nCLU in nonmalignant PNT1A cells, whereas only sCLU was found in cancer cells. Thus, CLU gene expression might play a crucial role in prostate tumorigenesis by exerting differential biological effects on normal versus tumor cells through differential processing of CLU isoforms in the two cell systems. We also found that nCLU binds to A-actinin, a key protein for the regulation of actin cytoskeleton, and that nCLU and A-actinin colocalize in the cytoplasm. Thus, the antimotility activity of nCLU and its ability to cause dismantling of the actin cytoskeleton seem to be mediated by its binding to A-actinin. [Cancer Res 2007; 67(21):10325-33]

mda‐7/IL‐24 Differentially Regulates Soluble and Nuclear Clusterin in Prostate Cancer

“…Accordingly, we document that nCLU production by MDA-7/IL-24 caused G 2 /M phase arrest followed by apoptosis. Furthermore, it has been reported that nCLU has potent anti-migratory activity through its binding to α-actinin (Moretti et al, 2007) and our present results revealed that nCLU generated by MDA-7/IL-24 is involved in altering cytoskeleton and resulted in decreased cell migration. Moreover, MDA-7/IL-24 decreased cell proliferation and colony formation with apoptosis induction in sCLU-overexpressing prostate cancer cells.…”

“…Overexpression of nCLU has been reported to induce G 2 /M phase arrest and caspase-dependent apoptosis in prostate cancer cells . Similarly, previous studies showed that transfection with "full-length" CLU cDNA produced both sCLU and nCLU in nonmalignant PNT1A cells, whereas only sCLU was found in cancer cells (Moretti et al, 2007). This escape mechanism limiting production of the proapoptotic nCLU from the full-length CLU gene might play a crucial role in prostate tumorigenesis.…”

“…There are two known CLU protein isoforms generated in human cells. A nuclear form of CLU protein (nCLU) which is pro-apoptotic, and a secretory (soluble) form (sCLU) that is pro-survival Trougakos et al, 2005;Shannan et al, 2006;Moretti et al, 2007). CLU protein translation produces a protein precursor that is targeted by an initial signal peptide to the endoplasmic reticulum, where it is cleaved into two distinct peptides (α and β) held together by five disulfide bonds.…”

IGF-1 activates the P13K/AKT signaling pathway via upregulation of secretory clusterin

“…It consists of 2 isoforms: secretory clusterin (sCLU) and intracellular clusterin (nCLU). The former has been described as a long-length CLU (also known as sCLU), while the latter as a nuclear form, truncated CLU (also known as nCLU) (9,10). sCLU is known as an extracellular secreted glycoprotein in the mature form that is upregulated in a variety of cell lines in response to stress and enhances cell survival (11).…”

Prognostic role of clusterin in resected adenocarcinomas of the lung

“…The progressive decrease of CLU expression is clearly one of the molecular changes implicated in the progression from pure BAC to invasive adenocarcinoma, and confirm the possible role of CLU as a tumor suppressor factor against infiltration or invasiveness. In fact, CLU has been already found as an important regulator of cell fate, negatively controlling further progression and invasiveness [12,32].…”