Clusterin is a widely expressed
glycoprotein that has been paradoxically observed to have both pro- and antiapoptotic functions. Recent reports suggest this apparent dichotomy of function may be related to two different
isoforms, one secreted and cytoplasmic, the other nuclear. To clarify the functional role of
clusterin in regulating apoptosis, we examined its expression in human
colon cancer tissues and in human
colon cancer cell lines. We additionally explored its expression and activity using models of
adenomatous polyposis coli (APC)- and
chemotherapy-induced apoptosis.
Clusterin RNA and
protein levels were decreased in
colon cancer tissues largely devoid of wild-type APC when compared with matched normal tissue controls, suggesting a means for invasive
cancers to avoid apoptosis. Conversely, induction of apoptosis by expression of wild-type APC or by treatment with
chemotherapy led to increased
clusterin RNA and
protein levels localizing to apoptotic nuclei. We found that transient transfection of
clusterin to
colon cancer cell lines directly enhanced basal and
chemotherapy-induced apoptosis.
Clusterin-induced apoptosis was inhibited by antisense
clusterin and was found to be highly dependent on p21 but not p53 expression, yet a deficit in p21 can be subverted by
clusterin transfection. Collectively, these data support the hypothesis that nuclear
clusterin function is proapoptotic when induced by APC or
chemotherapy in the context of p21 expression. Absent of p21,
clusterin in not induced, and apoptosis is significantly inhibited. These data support a potential therapeutic role for
clusterin in enhancing
chemotherapy-induced apoptosis and in promoting apoptosis in cells deficient in p21.