The human tumor suppressor CEACAM1 modulates apoptosis and is implicated in early colorectal tumorigenesis

Nittka, Stefanie; Günther, Juliane; Ebisch, Cornelia; Erbersdobler, Andreas; Neumaier, Michael

doi:10.1038/sj.onc.1208259

Cited by 79 publications

(83 citation statements)

References 42 publications

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“…Importantly, we found that this effect depends on the abundance of CEACAM1 at the cell membrane, since it was observed only in CEACAM1 high expressor HT29 cells but not in Activation and processing of CEACAM1 during apoptosis S Nittka et al HT29 cells that express only low amounts of CEA-CAM1. This finding indicates that CEACAM1 is the rate-limiting factor when apoptosis is induced which is consistent with our previous observation that loss of CEACAM1 is associated with reduced apoptosis in the early tumour lesions (Nittka et al, 2004). Because CEA and CEACAM1 are positioned in close spatial proximity at the plasma membrane of colonocytes (Baranov et al, 1994;Frangsmyr et al, 1995), our results provide a mechanistic basis through which CEA may be directly involved in the control of apoptosis in colon epithelial cells in vivo.…”

Section: Activation and Processing Of Ceacam1 During Apoptosis S Nittsupporting

confidence: 93%

“…CEACAM1 plays an important role in the morphogenesis in human breast tissues where it is associated with apoptosis in differentiating epithelial cells (Huang et al, 1999;Kirshner et al, 2003). We recently demonstrated that crosslinking of CEACAM1 on the cell surface of tumour cells mediates apoptosis (Nittka et al, 2004). Moreover, the loss of CEACAM1 is associated with reduced apoptosis in early colon tumour lesions in vivo, whereas normal apoptosis rates are found in CEACAM1-expressing tumours.…”

Section: Introductionmentioning

confidence: 92%

“…We previously demonstrated that antibodies directed against CEACAM1 induce programmed cell death in Jurkat cells (Nittka et al, 2004), suggesting that CEACAM1 is capable of activating the cellular apoptosis machinery. To gain more insight into the involvement of CEACAM1 in apoptosis pathways, we tested whether CEACAM1 is modified during apoptosis.…”

Section: Apoptosis Induces Dual Cleavage Of the Intracellular And Extmentioning

confidence: 99%

“…Apoptosis was induced by antibody-mediated crosslinking of CEACAM1 as described previously (Nittka et al, 2004) or incubation with human CEA (4-100 ng per well). Apoptosisdependent CEACAM1 processing was assessed in aliquots of 2 Â 10 6 cells which were incubated (16-24 h) with camptothecin (0.5 mM), etoposide (50 mM), cycloheximide (50-100 mM), actinomycin D (0.5-1 mM) and Fas-ligand (0.2 mg ml À1 ), respectively.…”

Section: Induction Of Apoptosismentioning

confidence: 99%

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The CEACAM1-mediated apoptosis pathway is activated by CEA and triggers dual cleavage of CEACAM1

et al. 2008

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Marked reduction in apoptosis is a hallmark of early colon tumour growth and the vast majority of these tumours exhibit a loss of expression of the glycoprotein carcinoembryonic-antigen-related cell adhesion molecule 1 (CEACAM1). We recently reported that the CEACAM1 functions as a mediator of apoptosis implicating this cell surface protein in early tumour development. However, the mechanistic involvement of CEACAM1 in cell death pathways is unclear. Here, we show that apoptosis triggers cleavage of the long form of CEACAM1 (CEACAM1-4L) at intracellular and extracellular sites in Jurkat cells and HEK293 cells. Signalling through CEACAM1 leads to caspase activation including caspase-1 and -3 and also involves non-caspase proteases. Moreover, we provide evidence that the naturally occurring CEACAM family member CEA is an inducer of CEACAM1-mediated apoptosis in HT29 colon cancer cells, an effect that depends on the abundance of CEACAM1 on the cell surface. Together, our results demonstrate that the CEACAM1-dependent cell death pathway involves dual cleavage of CEACAM1 and caspase activation and can be activated by CEA.

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Section: Activation and Processing Of Ceacam1 During Apoptosis S Nittsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 92%

Section: Apoptosis Induces Dual Cleavage Of the Intracellular And Extmentioning

confidence: 99%

Section: Induction Of Apoptosismentioning

confidence: 99%

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The CEACAM1-mediated apoptosis pathway is activated by CEA and triggers dual cleavage of CEACAM1

et al. 2008

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“…CEACAM1 downregulation is an early event in the genetic progression of colon cancer. Serial analysis of gene expression comparisons and DNA chip analyses show its absence in hyperplastic lesions, intestinal microadenomas and adenomas (Nollau et al, 1997;Buckhaults et al, 2001;Notterman et al, 2001;Nittka et al, 2004). CEACAM1 tumor suppressor activities are dependent upon the presence of its L cytoplasmic domain (Kunath et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Intestinal tumor progression is promoted by decreased apoptosis and dysregulated Wnt signaling in Ceacam1−/− mice

et al. 2008

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The carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) is downregulated in colonic and intestinal hyperplastic lesions as well as in other cancers, where it functions as a tumor suppressor. To investigate the functions of CEACAM1 in the normal intestine and in intestinal tumors, we generated a compound knockout mouse model and examined both Ceacam1 À/À and Apc 1638N/ þ :Ceacam1 À/À mice. Ceacam1 À/À intestinal cells exhibited a significant decrease in apoptosis, with no change in proliferation or migration, however. Compound Apc 1638N/ þ :Ceacam1 À/À mice demonstrated an increase in intestinal tumor multiplicity and tumor progression. Increases in intussusceptions and desmoid lesions were also observed. We have shown that CEACAM1-L associates with b-catenin by co-immunoprecipitation and colocalization in CEACAM1-L-transfected CT26 and CT51 mouse colon carcinoma cells. Ceacam1 À/À enterocytes displayed decreased glycogen synthase kinase 3-b activity with corresponding nuclear localization of b-catenin. Increased T-cell factor/Lef transcriptional activity was observed in CEACAM1-null CT51 colonic cells and in Caco2 colon cancer cells in which CEACAM1 was downregulated. A significant increased expression in c-Myc and cyclin D1 targets of the Wnt signaling pathway was also revealed in the Ceacam1 À/À intestine. CEACAM1 therefore actively participates in Wnt signaling in intestinal cells and its downregulation in intestinal tissue contributes to malignancy by augmenting tumor multiplicity and progression.

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Re‐expression of CEACAM1 long cytoplasmic domain isoform is associated with invasion and migration of colorectal cancer

Ieda

Yokoyama

Tamura

et al. 2011

Intl Journal of Cancer

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Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is known to be downregulated at the transcriptional level in adenoma and carcinoma. Recent reports have shown that CEACAM1 is overexpressed at protein level in colorectal cancer and correlated with clinical stage. The reason why colorectal cancer cells re-expressed CEACAM1 remains unclear. The aim of our study was to clarify the implication of CEACAM1 re-expression in colorectal cancer. Immunohistochemical analyses were conducted with CEACAM1 long (CEACAM1-L) or short (CEACAM1-S) cytoplasmic domain-specific antibodies on clinical samples from 164 patients with colorectal cancer. The risk factors for metastasis and survival were calculated for clinical implication of CEACAM1 re-expression. Invasion chamber and wound healing assays were performed for the effect of CEACAM1 expression on invasion and migration of colorectal cancer cells. CEACAM1-L and CEACAM1-S stained with greater intensity at the invasion front than at the luminal surface of tumors. Differences between the long and short cytoplasmic isoform expression levels were observed at the invasion front. Multivariate analysis showed that CEACAM1-L dominance was an independent risk factor for lymph node metastasis, hematogenous metastasis and short survival. The Kaplan-Meier evaluation demonstrated that CEACAM1-L dominance was associated with shorter survival time (p < 0.0001). In the invasion chamber and wound healing assays, CEACAM1-L promoted invasion and migration. Re-expression of CEACAM1 is observed at the invasion front of colorectal cancer. CEACAM1-L dominance is associated with metastasis and shorter survival of the patients with colorectal cancer. CEACAM1-L dominance is important for colorectal cancer cells invasion and migration.

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The human tumor suppressor CEACAM1 modulates apoptosis and is implicated in early colorectal tumorigenesis

Cited by 79 publications

References 42 publications

The CEACAM1-mediated apoptosis pathway is activated by CEA and triggers dual cleavage of CEACAM1

The CEACAM1-mediated apoptosis pathway is activated by CEA and triggers dual cleavage of CEACAM1

Intestinal tumor progression is promoted by decreased apoptosis and dysregulated Wnt signaling in Ceacam1−/− mice

Re‐expression of CEACAM1 long cytoplasmic domain isoform is associated with invasion and migration of colorectal cancer

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