Clusterin-Mediated Apoptosis Is Regulated by Adenomatous Polyposis Coli and Is p21 Dependent but p53 Independent

Abstract

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 wildtype 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.

Clusterin Expression in Normal Mucosa and Colorectal Cancer

“…Although some reports have indicated CLU to be up-regulated in neoplastic colorectal tissues (7,15), others have indicated down-regulation (16). This apparent discrepancy is not unique for studies investigating CLU expression in CRC as it has also been reported for prostate cancer (1).…”

“…However, previous studies on CLU expression in CRC have disagreed on whether CLU is up-regulated (7,15) or downregulated by the cancer cells (16). There are many possible explanations for the inconsistent observations, e.g.…”

Transcriptome analysis of peripheral blood mononuclear cells in human subjects following a 36 h fast provides evidence of effects on genes regulating inflammation, apoptosis and energy metabolism

“…following the extended fast, is increased in parallel with increased CDKN1A in response to oxidative and other cellular stresses (Han et al 2008) and in liver following treatment with glucocorticoids; hormones that help to regulate blood glucose during fasting (Wong et al 2010). Expression of clusterin at the level of mRNA is, at least in part, dependent on CDKN1A (Chen et al 2004). Clusterin, for which the mRNA levels increased following the extended fast, is a regulator of apoptosis and its expression is used as a marker of cell senescence (Petropoulou et al 2001;Trougakos et al 2006).…”

Genetic inactivation of ApoJ/clusterin: effects on prostate tumourigenesis and metastatic spread

“…Moreover, we also found that CLU expression is down-regulated during prostate cancer progression in the TRAMP mouse model . When overexpressed, CLU causes growth inhibition and death of prostate cell lines, as a consequence of nuclear accumulation (Caccamo et al, 2003(Caccamo et al, , 2005Chen et al, 2004). One of the possible explanations for the contrasting biological effects of CLU in different settings is that it can shuttle between the outside and inside the cell.…”