Chronic cadmium exposure induces transcriptional activation of the Wnt pathway and upregulation of epithelial-to-mesenchymal transition markers in mouse kidney

Chakraborty, Prabir K.; Scharner, Bettina; Jurasović, Jasna; Meßner, Barbara; Bernhard, David; Thévenod, Frank

doi:10.1016/j.toxlet.2010.05.007

Cited by 55 publications

(34 citation statements)

References 56 publications

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“…Altogether, this underlines the ability of Cd 2ϩ to act indirectly as a strong carcinogen. Recently, Cd 2ϩ has been found to induce Wnt signaling in kidney cells by disrupting the E-cadherin/␤-catenin complex (31), and in mice chronic Cd 2ϩ exposure has been found to up-regulate both Wnt ligands, Wnt receptors and Wnt activated genes in the kidney (37). These data, in addition to our findings, indicate a possible feedback mechanism for Wntpathway activity and cellular Cd 2ϩ uptake.…”

Section: Discussionsupporting

confidence: 81%

Alternative Splicing of SLC39A14 in Colorectal Cancer is Regulated by the Wnt Pathway

Thorsen

Mansilla

Schepeler

et al. 2011

Molecular & Cellular Proteomics

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Alternative splicing is a crucial step in the generation of protein diversity and its misregulation is observed in many human cancer types. By analyzing 143 colorectal samples using exon arrays, SLC39A14, a divalent cation transporter, was identified as being aberrantly spliced in tumor samples. SLC39A14 contains two mutually exclusive exons 4A and 4B and the exon 4A/4B ratio was significantly altered in adenomas (p ‫؍‬ 3.6 ؋ 10 ؊10 ) and cancers (p ‫؍‬ 9.4 ؋ 10 ؊11 ), independent of microsatellite stability status. The findings were validated in independent exon array data sets and by quantitative real-time reverse-transcription PCR (qRT-PCR). Aberrant Wnt signaling is a hallmark of colorectal tumorigenesis and is characterized by nuclear ␤-catenin. Experimental inactivation of Wnt signaling in DLD1 and Ls174T cells by knockdown of ␤-catenin or overexpression of dominant negative TCFs (TCF1 and TCF4) altered the 4A/4B ratio, indicating that SLC39A14 splicing is regulated by the Wnt pathway. An altered 4A/4B ratio was also observed in gastric and lung cancer where Wnt signaling is also known to be aberrantly activated. The splicing factor SRSF1 and its regulator, the kinase SRPK1, were found to be deregulated upon Wnt inactivation in colorectal carcinoma cells. SRPK1 was also found up-regulated in both adenoma samples (p ‫؍‬ 1.5 ؋ 10 ؊5 ) and cancer samples (p ‫؍‬ 5 ؋ 10 ؊4 ). In silico splicing factor binding analysis predicted SRSF1 to bind predominantly to the cancer associated exon 4B, hence, it was hypothesized that SRPK1 activates SRSF1 through phosphorylation, followed by SRSF1 binding to exon 4B and regulation of SLC39A14 splicing. Indeed, siRNA-mediated knockdown of SRPK1 and SRSF1 in DLD1 and SW480 colorectal cancer cells led to a change in the 4A/4B isoform ratio, supporting a role of these factors in the regulation of SLC39A14 splicing. In conclusion, alternative splicing of SLC39A14 was identified in colorectal tumors and found to be regulated by the Wnt pathway, most likely through regulation of SRPK1 and SRSF1. Molecular &

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Section: Discussionsupporting

confidence: 81%

Alternative Splicing of SLC39A14 in Colorectal Cancer is Regulated by the Wnt Pathway

Thorsen

Mansilla

Schepeler

et al. 2011

Molecular & Cellular Proteomics

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“…Previous studies from our laboratories and more recent studies by Thévenod and coworkers (Prozialeck et al, 2002;Thévenod et al, 2007;Thévenod, 2009;Chakraborty et al, 2010;Thévenod and Chakraborty, 2010) have provided evidence that the disruption of cadherin-mediated adhesion by cadmium results in the nuclear accumulation of ␤-catenin and activation of ␤-catenin-regulated gene expression. The study by Chakraborty et al (2010) is particularly significant.…”

Section: Cadherin Cell Adhesion Molecules As Potential Targets Of Cadmentioning

confidence: 88%

“…The study by Chakraborty et al (2010) is particularly significant. Using an in vivo mouse model of long-term cadmium ingestion, the investigators showed that cadmium caused the upregulation in the expression of specific Wnt ligands and receptors that coincided with increases in the expression of several ␤-catenin-regulated genes including c-myc, cyclin D1, and Abcb1.…”

Section: Cadherin Cell Adhesion Molecules As Potential Targets Of Cadmentioning

confidence: 99%

Mechanisms of Cadmium-Induced Proximal Tubule Injury: New Insights with Implications for Biomonitoring and Therapeutic Interventions

Prozialeck

Edwards

2012

J Pharmacol Exp Ther

220

150

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Cadmium is an important industrial agent and environmental pollutant that is a major cause of kidney disease. With chronic exposure, cadmium accumulates in the epithelial cells of the proximal tubule, resulting in a generalized reabsorptive dysfunction characterized by polyuria and low-molecular-weight proteinuria. The traditional view has been that as cadmium accumulates in proximal tubule cells, it produces a variety of relatively nonspecific toxic effects that result in the death of renal epithelial cells through necrotic or apoptotic mechanisms. However, a growing volume of evidence suggests that rather than merely being a consequence of cell death, the early stages of cadmium-induced proximal tubule injury may involve much more specific changes in cell-cell adhesion, cellular signaling pathways, and autophagic responses that occur well before the onset of necrosis or apoptosis. In this commentary, we summarize these recent findings, and we offer our own perspectives as to how they relate to the toxic actions of cadmium in the kidney. In addition, we highlight recent findings, suggesting that it may be possible to detect the early stages of cadmium toxicity through the use of improved biomarkers. Finally, some of the therapeutic implications of these findings will be considered. Because cadmium is, in many respects, a model cumulative nephrotoxicant, these insights may have broader implications regarding the general mechanisms through which a variety of drugs and toxic chemicals damage the kidney.

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“…This raises the potential that the HSR may stimulate a variety of cellular properties that are required for tumour recurrence and aggressive cancer cell phenotypes. A number of studies have shown that various forms of proteotoxic stress such as hypoxia, proteasome inhibition, ethanol treatment, endoplasmic reticulum (ER) stress, and oxidative stress-induced cell migration, invasion and EMT (Cannito et al 2008;Chakraborty et al 2010;Mak et al 2010;Tamminen et al 2012;Zhong et al 2011 treatments such as hyperthermia treatment and pharmacological inhibition of the proteasome illicit proteotoxic stress and activate the HSR in tumour cells, their ability to promote aggressive cancer phenotypes has not been fully examined. Therefore, the aim of the current study was to determine whether proteotoxic stress, primarily in the form of heat stress, could promote advanced cancer phenotypes such as enhancing epithelial plasticity and cell migration.…”

Section: Discussionmentioning

confidence: 99%

“…The importance of determining the underlying mechanisms that enable tumour recurrence and their refractory nature to treatments is exemplified by the fact that clinical response to therapy often does not correlate with extended patient overall survival in advanced cancers (Huff et al 2006;Blagosklonny 2005b). Recent studies have shown that in addition to activating pathways that confer enhanced cell survival, various forms of proteotoxic stress can promote properties associated with a more aggressive cell phenotype such as enhanced cell migration, invasion and epithelial-tomesenchymal transition (EMT; Cannito et al 2008;Mak et al 2010;Zhong et al 2011;Chakraborty et al 2010;Tamminen et al 2012;Forsyth et al 2010). These studies suggest that in the likely event that therapies such as hyperthermic chemotherapy, radiation therapy and chemotherapeutics are not sufficient in causing tumour cell death, the proteotoxic stress undergone by surviving cells may actively progress these cells towards more aggressive phenotypes.…”

Section: Introductionmentioning

confidence: 99%

Heat stress induces epithelial plasticity and cell migration independent of heat shock factor 1

Lang

Nguyen

et al. 2012

Cell Stress and Chaperones

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Current cancer therapies including cytotoxic chemotherapy, radiation and hyperthermic therapy induce acute proteotoxic stress in tumour cells. A major challenge to cancer therapeutic efficacy is the recurrence of therapyresistant tumours and how to overcome their emergence. The current study examines the concept that tumour cell exposure to acute proteotoxic stress results in the acquisition of a more advanced and aggressive cancer cell phenotype. Specifically, we determined whether heat stress resulted in an epithelial-to-mesenchymal transition (EMT) and/or the enhancement of cell migration, components of an advanced and therapeutically resistant cancer phenotype. We identified that heat stress enhanced cell migration in both the lung A549, and breast MDA-MB-468 human adenocarcinoma cell lines, with A549 cells also undergoing a partial EMT. Moreover, in an in vivo model of thermally ablated liver metastases of the mouse colorectal MoCR cell line, immunohistological analysis of classical EMT markers demonstrated a shift to a more mesenchymal phenotype in the surviving tumour fraction, further demonstrating that thermal stress can induce epithelial plasticity. To identify a mechanism by which thermal stress modulates epithelial plasticity, we examined whether the major transcriptional regulator of the heat shock response, heat shock factor 1 (HSF1), was a required component. Knockdown of HSF1 in the A549 model did not prevent the associated morphological changes or enhanced migratory profile of heat stressed cells. Therefore, this study provides evidence that heat stress significantly impacts upon cancer cell epithelial plasticity and the migratory phenotype independent of HSF1. These findings further our understanding of novel biological downstream effects of heat stress and their potential independence from the classical heat shock pathway.

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Chronic cadmium exposure induces transcriptional activation of the Wnt pathway and upregulation of epithelial-to-mesenchymal transition markers in mouse kidney

Cited by 55 publications

References 56 publications

Alternative Splicing of SLC39A14 in Colorectal Cancer is Regulated by the Wnt Pathway

Alternative Splicing of SLC39A14 in Colorectal Cancer is Regulated by the Wnt Pathway

Mechanisms of Cadmium-Induced Proximal Tubule Injury: New Insights with Implications for Biomonitoring and Therapeutic Interventions

Heat stress induces epithelial plasticity and cell migration independent of heat shock factor 1

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