Intracellular clusterin induces G2-M phase arrest and cell death in PC-3 prostate cancer cells1

Cancer Research
M ScaltritiSaverio Bettuzzi

Abstract

Enhanced clusterin gene expression has been related frequently to organ remodeling, tissue involution, and cell death. Whether clusterin represents a leading cause or a consequence of apoptosis induction is still a matter of debate. Clusterin is known as an extracellular secreted glycoprotein in the mature form. However, truncated isoforms of the protein and nuclear localization of clusterin have been described recently in association to cell death. Here, we show the biological effects triggered in PC-3 androgen-independent prostate cancer cells by overexpression of an intracellular, not secreted form of clusterin (intracellular-clusterin). Transient transfection of PC-3 cells with intracellular-clusterin resulted in nuclear localization signal-independent massive nuclear localization of the protein leading to G2-M phase blockade followed by caspase-dependent apoptosis. Constitutive expression of intracellular-clusterin (pFLAG- intracellular-clusterin) in recombinant PC-3 cells caused clonogenic toxicity. The rare pFLAG-intracellular clusterin surviving clones showed inhibition of the proliferation rate and altered phenotype with impaired mitosis and endoreduplication. In these cells, caspase-independent cell death was induced....Continue Reading

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