Response to a lethal dose of heat shock by a transient up‐regulation of clusterin expression followed by down‐regulation and apoptosis in prostate and bladder cancer cells

Wu, Angela; Park, Irwin I.; Zhaung, Lei; Lee, Chung

doi:10.1002/pros.10158

Cited by 19 publications

(16 citation statements)

References 20 publications

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“…For example, oxidative stress of human diploid fibroblasts [22,35] or C 2 -ceramide-treatment of pancreatic cells [36] induced anti-proliferative responses and up-regulated clusterin/apoJ perhaps as an attempt to survive. In contrast, apoptotic stimuli such as UVB irradiation, dexamethasone-treatment [37], chemotherapeutic agents [23,38] or heat shock [39] induced apoptosis by markedly decreasing the expression of clusterin/ApoJ, in a dose-and time-dependent manner [23]. The downregulation of clusterin/apoJ in keratinocytes undergoing ropivacaine-mediated apoptosis is in agreement with previous studies [40].…”

Section: Discussionsupporting

confidence: 89%

Ectopic expression of clusterin/apolipoprotein J or Bcl-2 decreases the sensitivity of HaCaT cells to toxic effects of ropivacaine

et al. 2004

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Local anesthetics inhibit cell proliferation and induce apoptosis in various cell types. Ropivacaine, a unique, novel tertiary amine-type anesthetic, was shown to inhibit the proliferation of several cell types including keratinocytes. We found that Ropivacaine could inhibit the proliferation and induce apoptosis in an immortalized human keratinocyte line, HaCaT, in a dose-and time-dependent manner and with the deprivation of serum. The dose-dependent induction of apoptosis by ropivacaine was demonstrated by DNA fragmentation analysis and the proteolytic cleavage of a caspase-3 substrate -poly (ADP-ribose) polymerase (PARP). In addition, ropivacaine downregulated the expression of clusterin/ apoliporotein J, a protein with anti-apoptotic properties, in a dose-dependent manner, which well correlated with the induction of apoptosis of HaCaT cells. To investigate the role of clusterin/apoliporotein J in ropivacaine-induced apoptosis, HaCaT cells overexpressing clusterin/apoliporotein J were generated and compared to cells expressing the well established anti-apoptotic Bcl-2 protein. Ectopic overexpression of the secreted form of clusterin/apoliporotein J or Bcl-2 decreased the sensitivity of HaCaT cells to toxic effects of ropivacaine as demonstrated by DNA fragmentation, the proteolytic cleavage of PARP and by a reduction in procaspase-3 expression. Furthermore, the downregulation of endogenous clusterin/apolipoprotein J levels by ropivacaine suggested that this might be one mechanism by which ropivacaine induced cell death in HaCaT cells. In conclusion, the ability of ropivacaine to induce antiproliferative responses and to suppress the expression of the anti-apoptotic protein clusterin/apolipoprotein J, combined with previously reported anti-inflammatory activity and analgesic property of the drug, suggests that ropivacaine may have potential utility in the local treatment of tumors.

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Section: Discussionsupporting

confidence: 89%

Ectopic expression of clusterin/apolipoprotein J or Bcl-2 decreases the sensitivity of HaCaT cells to toxic effects of ropivacaine

et al. 2004

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“…Depending on the cell metabolic contest and stimulus, clusterin would have both pro-and anti-apoptotic properties, probably because of different protein products (clusterin isoforms) coded by the same gene. In this view, a secreted form of clusterin would act as a cytoprotective protein (31)(32)(33), also acting as an extracellular chaperone-inducing phagocytosis (34,35), although a nuclear form, possibly starting from a second in-frame ATG, was suggested to be a cell death protein (18,20). As a consequence of different pro-apoptotic stimuli (and/or through different mechanisms not elucidated completely yet), the biosynthesis of a not-secreted, truncated form of clusterin would take place in the cell, and its accumulation would commit cells to apoptotic death.…”

Section: Discussionmentioning

confidence: 99%

Intracellular Clusterin Induces G2-M Phase Arrest and Cell Death in PC-3 Prostate Cancer Cells1

Scaltriti

Santamaría²,

Paciucci³

et al. 2004

Cancer Research

100

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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 G 2 -M phase blockade followed by caspase-dependent apoptosis. Constitutive expression of intracellular-clusterin (pFLAGintracellular-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. Impaired cell cycle progression in pFLAG-intracellular-clusterin clones was associated to arrest at the G 2 -M checkpoint by down-regulation of the mitotic complex cyclin B1/cyclin-dependent kinase 1. Intriguingly, intracellular-clusterin was localized exclusively in the cytoplasm in stably transfected cells, suggesting a negative correlation between nuclear clusterin accumulation and cell survival. These findings may possibly explain the conflicting results obtained in different laboratories, suggesting that clusterin might be a proapoptotic or a survival gene, also opening new perspectives for the characterization of androgenindependent and apoptosis-resistant prostate cancer cells.

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“…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). However, a number of studies have demonstrated that sCLU can also act as a cytoprotective protein (12)(13)(14). nCLU with nuclear localization has recently been described to be associated with cell death (15).…”

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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Response to a lethal dose of heat shock by a transient up‐regulation of clusterin expression followed by down‐regulation and apoptosis in prostate and bladder cancer cells

Abstract: Clusterin offers a protection to PC-3 and TSU-Prl cells against heat shock and plays an important role in the cascade of events initiated by heat shock. Prostate 53: 277-285, 2002.

Cited by 19 publications

References 20 publications

Ectopic expression of clusterin/apolipoprotein J or Bcl-2 decreases the sensitivity of HaCaT cells to toxic effects of ropivacaine

Ectopic expression of clusterin/apolipoprotein J or Bcl-2 decreases the sensitivity of HaCaT cells to toxic effects of ropivacaine

Intracellular Clusterin Induces G2-M Phase Arrest and Cell Death in PC-3 Prostate Cancer Cells1

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

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