Inhibition of the Proliferative Cycle and Apoptotic Events in WiDr Cells after Down-Regulation of the Calcium-Binding Protein Calretinin Using Antisense Oligodeoxynucleotides

Gander, J C; Gotzos, V.; Fellay, Benoı̂t; Schwaller, Beat

doi:10.1006/excr.1996.0191

Cited by 43 publications

(39 citation statements)

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“…It is a member of the EF-hand family of proteins, with expression limited to several distinct tissues including central nervous tissues and excitable cells, interstitial cells of the rat ovary (12), avian thymus tissue (13), and colorectal carcinoma cells (14). The specific function of calretinin still remains to be elucidated but a role in intracellular Ca 2+ movement has been suggested in excitable cells and a role in cell cycle progression in nonexcitable tissue (15). In the present study, calretinin was identified in the microarray analysis as one of several calcium-binding proteins that were upregulated in response to oxaliplatin treatment (2.0-fold; Table 2).…”

Section: Resultsmentioning

confidence: 61%

Pharmacogenomic Identification of Novel Determinants of Response to Chemotherapy in Colon Cancer

et al. 2006

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DNA microarray analysis was used to analyze the transcriptional profile of HCT116 colorectal cancer cells that were treated with 5-fluorouracil (5-FU) or oxaliplatin and selected for resistance to these agents. Bioinformatic analyses identified sets of genes that were constitutively dysregulated in drug-resistant cells and transiently altered following acute exposure of parental cells to drug. We propose that these genes may represent molecular signatures of sensitivity to 5-FU and oxaliplatin. Using real-time reverse transcription-PCR (RT-PCR), the robustness of our microarray data was shown with a strong overall concordance of expression trends for z82% (oxaliplatin) and z85% (5-FU) of a representative subset of genes. Furthermore, strong correlations between the microarray and real-time RT-PCR measurements of average fold changes in gene expression were observed for both the 5-FU (R 2 z 0.73) and oxaliplatin gene sets (R 2 z 0.63). Functional analysis of three genes identified in the microarray study [prostate-derived factor (PDF), calretinin, and spermidine/spermine N 1 -acetyl transferase (SSAT)] revealed their importance as novel regulators of cytotoxic drug response. These data show the power of this novel microarray-based approach to identify genes which may be important markers of response to treatment and/or targets for therapeutic intervention. (Cancer Res 2006; 66(5): 2765-77)

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Section: Resultsmentioning

confidence: 61%

Pharmacogenomic Identification of Novel Determinants of Response to Chemotherapy in Colon Cancer

et al. 2006

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“…The question remains if the two phenomena, namely the concentration of either CR or CR-22k and the proliferation of these cells are directly correlated. Previously we have down-regulated the expression of calretinins with antisense oligodeoxynucleotides (Gander et al, 1996b) and we could demonstrate that downregulation of CR and CR-22k lead to an inhibition of proliferation. This demonstrated that the presence of calretinins in WiDr cells seemed to be a prerequisite for their proliferative status.…”

Section: Effects Of 125-(oh) 2 D3 or Hmba+nabt On The Level And Subcmentioning

confidence: 76%

Regulated redistribution of calretinins in WiDr cells

Schwaller

Herrmann

1997

Cell Death Differ

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The calcium-binding protein calretinin and the alternatively spliced form calretinin-22k are expressed in the colon adenocarcinoma cell line WiDr. As calcium-binding proteins have been implicated to play a role in cell cycle control, proliferation and differentiation, the levels and intracellular localisation of these two proteins were investigated. The addition of 1,25-dihydroxy vitamin D3 (10 78 M) led to a transient translocation of calretinin-22k into the nucleus, while the cell growth was not affected. The addition of sodium butyrate and hexamethylene bisacteamide which induce markers of enterocyte differentiation decreased the levels of both forms of calretinin more than 90%. The agents which induced differentiation also led to a substantial inhibition of 3 H-thymidine incorporation (495%) which was paralleled by the disappearance of calretinins. We conclude that calretinin and calretinin-22k are associated with the proliferative status of WiDr cells and are almost completely absent in differentiated cells.

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“…Since the induction of a more differentiated phenotype in WiDr or HT-29 cells by either butyrate [Marilley et al, 2001] or glucose starvation [Cargnello et al, 1996], respectively, goes together with a decrease in CR expression, we hypothesize that 5-FU and oxaliplatin are more efficient cytotoxic agents in proliferating cells in vitro than in ones, where the cell cycle is already entirely blocked. Knockdown of CR expression by antisense oligo nucleotides in WiDr cells blocks the cycle mainly at G1/S [Gander et al, 1996]. Thus, this apparent protection against 5-FU cytotoxicity might be due to the cell cycle silencing effect induced by CR downregulation.…”

Section: Discussionmentioning

confidence: 98%

“…Many colon cancer cell lines used as models to investigate tumorigenesis (e.g., WiDr), express high levels of CR [Gotzos et al, 1996a]. A role for CR in tumor biogenesis was postulated based on two findings: I) Downregulation of CR by antisense methods blocks the cell cycle at G1/S and leads to increased apoptosis [Gander et al, 1996] closely resembling the effects of butyrate and II) Overexpression of CR or the alternatively splice product CR-22k [Schwaller et al, 1995] increases the resistance of the CR-negative cell line Caco-2 towards butyrateinduced growth inhibition and differentiation [Marilley et al, 2001]. Thus, we investigated whether the promoter region of the CALB2 gene contains butyrate-responsive elements (BRE) acting as transcriptional repressors and whether these putative elements are functional in different types of CR-positive cells including colon cancer cells and cells of mesothelial origin.…”

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confidence: 99%

A bipartite butyrate‐responsive element in the human calretinin (CALB2) promoter acts as a repressor in colon carcinoma cells but not in mesothelioma cells

Häner

Henzi

Pfefferli

et al. 2009

J of Cellular Biochemistry

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The short-chain fatty acid butyrate plays an essential role in colonic mucosa homeostasis through the capacity to block the cell cycle, regulate differentiation and to induce apoptosis. The beneficial effect of dietary fibers on preventing colon cancer is essentially mediated through butyrate, derived from luminal fermentation of fibers by intestinal bacteria. In epithelial cells of the colon, both in normal and colon cancer cells, the expression of several genes is positively or negatively regulated by butyrate likely through modulation of histone acetylation and thereby affecting the transcriptional activity of genes. Calretinin (CALB2) is a member of the EF-hand family of Ca 2þ -binding proteins and is expressed in a majority of poorly differentiated colon carcinoma and additionally in mesothelioma of the epithelioid and mixed type. Since CALB2 is one of the genes negatively regulated by butyrate in colon cancer cells and butyrate decreases calretinin protein expression levels in those cells, we investigated whether expression is regulated via putative butyrate-responsive elements (BRE) in the human CALB2 promoter. We identified two elements that act as butyrate-sensitive repressors in all colon cancer cell lines tested (CaCo-2, HT-29, Co-115/3). In contrast, in cells of mesothelial origin, MeT-5A and ZL34, the same two elements do not operate as butyrate-sensitive repressors and calretinin expression levels are insensitive to butyrate indicative of cell type-specific regulation of the CALB2 promoter. Calretinin expression in colon cancer cells is negatively regulated by butyrate via a bipartite BRE flanking the TATA box and this may be linked to butyrate's chemopreventive activity.

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Inhibition of the Proliferative Cycle and Apoptotic Events in WiDr Cells after Down-Regulation of the Calcium-Binding Protein Calretinin Using Antisense Oligodeoxynucleotides

Cited by 43 publications

References 0 publications

Pharmacogenomic Identification of Novel Determinants of Response to Chemotherapy in Colon Cancer

Pharmacogenomic Identification of Novel Determinants of Response to Chemotherapy in Colon Cancer

Regulated redistribution of calretinins in WiDr cells

A bipartite butyrate‐responsive element in the human calretinin (CALB2) promoter acts as a repressor in colon carcinoma cells but not in mesothelioma cells

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