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

Moretti, Roberta M.; Marelli, Marina Montagnani; Mai, Stefania; Cariboni, Anna; Scaltriti, Maurizio; Bettuzzi, Saverio; Limonta, Patrizia

doi:10.1158/0008-5472.can-07-0516

Cited by 55 publications

(55 citation statements)

References 51 publications

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“…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.…”

Section: Discussionsupporting

confidence: 71%

“…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.…”

Section: Introductionsupporting

confidence: 63%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Bhutia¹,

Das²,

Kegelman³

et al. 2013

Journal Cellular Physiology

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Melanoma differentiation-associated , a unique member of the IL-10 gene family, displays a broad range of antitumor properties including cancer-specific induction of apoptosis, inhibition of tumor angiogenesis, and modulation of anti-tumor immune responses. Here we identify clusterin (CLU) as a MDA-7/IL-24 interacting protein in DU-145 cells and investigate the role of MDA-7/IL-24 in regulating CLU expression and mediating the antitumor properties of mda-7/IL-24 in prostate cancer. Ad.mda-7 decreased expression of soluble CLU (sCLU) and increased expression of nuclear CLU (nCLU). In the initial phase of Ad.mda-7 infection sCLU expression increased and CLU interacted with MDA-7/IL-24 producing a cytoprotective effect. Infection of stable clones of DU-145 prostate cancer cells expressing sCLU with Ad.mda-7 resulted in generation of nCLU that correlated with decreased cell viability and increased apoptosis. In the presence of mda-7/IL-24, sCLU-DU-145 cells displayed G 2 /M phase arrest followed by apoptosis. Similarly, Ad.mda-7 infection decreased cell migration by altering cytoskeleton in sCLU-DU-145 cells. Ad.mda-7-treated sCLU-DU-145 cells displayed a significant reduction in tumor growth in mouse xenograft models and reduced angiogenesis when compared to the vector control group. Tumor tissue lysates demonstrated enhanced nCLU generated from NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript sCLU with increased apoptosis in the presence of MDA-7/IL-24. Our findings reveal novel aspects relative to the role of sCLU/nCLU in regulating the anticancer properties of MDA-7/IL-24 that may be exploited for developing enhanced therapies for prostate cancer.

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Section: Discussionsupporting

confidence: 71%

Section: Introductionsupporting

confidence: 63%

Section: Introductionmentioning

confidence: 99%

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

Bhutia¹,

Das²,

Kegelman³

et al. 2013

Journal Cellular Physiology

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“…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).…”

Section: Introductionmentioning

confidence: 99%

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

Bai

2012

Molecular Medicine Reports

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Abstract. Secretory clusterin (sCLU) is a type of stressinduced, pro-survival glycoprotein elevated in early-stage cancer. It enhances cancer cell survival and is associated with several types of cancer progression. In this study, we measured the PI3K/AKT signaling activity by determining the phosphorylation level of the AKT protein, namely pAKT. A549 human non-small cell lung carcinoma (NSCLC) cells were treated with insulin-like growth factor-1 (IGF-1) for various periods of time.The results showed that IGF-1 activated the PI3K/AKT signaling pathway in the A549 cells in a time-dependent manner. Western blot analysis was performed to determine the expression of sCLU protein in A549 cells treated with IGF-1. IGF-1 elevated the expression of sCLU. To determine whether sCLU is required for the IGF-1 activation of the PI3K/AKT signaling pathway, the A549 cells were treated with IGF-1 and sCLU antisense oligonuleotide (sCLU ASO). sCLU ASO blocked the IGF-1 activation of the PI3K/AKT signaling pathway. These results demonstrate that IGF-1 activates the P13K/AKT signaling pathway via the upregulation of sCLU. The present study implies that this pathway may uncover a new mechanism for cancer progression and reveal new targets for drug development in the treatment of NSCLC.

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“…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].…”

Section: Discussionmentioning

confidence: 99%

Prognostic role of clusterin in resected adenocarcinomas of the lung

et al. 2013

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a b s t r a c tRationale: Clusterin expression may change in various human malignancies, including lung cancer. Patients with resectable non-small cell lung cancer (NSCLC), including adenocarcinoma, have a poor prognosis, with a relapse rate of 30-50% within 5 years. Nuclear factor kB (Nf-kB) is an intracellular protein involved in the initiation and progression of several human cancers, including the lung. Objectives: We investigate the role of clusterin and Nf-kB expression in predicting the prognosis of patients with early-stage surgically resected adenocarcinoma of the lung. Findings: The level of clusterin gradually decreased from well-differentiated to poorly differentiated adenocarcinomas. Clusterin expression was significantly higher in patients with low-grade adenocarcinoma, in early-stage disease and in women. Clusterin expression was inversely related to relapse and survival in both univariate and multivariate analyses. Finally, we observed an inverse correlation between Nf-kB and clusterin. Conclusions: Clusterin expression represents an independent prognostic factor in surgically resected lung adenocarcinoma and was proven to be a useful biomarker for fewer relapses and longer survival in patients in the early stage of disease. The inverse correlation between Nf-kB and clusterin expression confirm the previously reported role of clusterin as potent down regulator of Nf-kB.

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

Cited by 55 publications

References 51 publications

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

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

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

Prognostic role of clusterin in resected adenocarcinomas of the lung

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