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

Abstract

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.

CEA is an Independent Prognostic Indicator that is Associated with Reduced Survival and Liver Metastases in SCLC

“…We found that high CEA level was expression was also associated with liver metastases in SCLC, which may account for the poor survival of these patients. Previous studies have shown that CEA was associated with several physiopathological processes of tumorigenesis, such as immunological defense, cell adhesion, cell survival, and metastasis [18,19]. Expression of CEA has been reported to be induced by hypoxia-inducible factor a (HIF-a), suggesting that CEA may play an important role as a microenvironmental factor during tumorigenesis and thereby confer a worse prognosis [20].…”

Dendritic Cell-specific Intercellular Adhesion Molecule 3-grabbing Non-integrin (DC-SIGN) Recognizes a Novel Ligand, Mac-2-binding Protein, Characteristically Expressed on Human Colorectal Carcinomas

“…In general, these changes have been associated with a poor prognosis, as they are linked to the aggressiveness and metastatic capacity of tumors. Good examples of heavily glycosylated tumor antigens are CEA and CEACAM1 (13)(14)(15)(16)(17)(18)(19), which can be secreted or expressed by colon cancer cells. Because the function of dendritic cells may be dependent on their binding properties as to self-antigens and pathogens, it is essential to obtain a detailed insight into the carbohydrate-binding properties of DC-SIGN.…”

Loss of Expression of the Tumor Suppressor CEACAM1 Links Different Hereditary Colorectal Carcinoma Subtypes to the Genesis of Sporadic Colorectal Carcinoma

“…In any case, the b-catenin immunohistochemical analysis confirms that deregulation of theWntpathwayisnotacommoncarcinogenicmechanismin these subgroups of tumors. Taken together, we have shown that the alterations in the expression of CEACAMs, most notablyofCEACAM1,occurindifferenttypesofhereditary CRCwiththeclinicalphenotypeofHNPCCs.Togetherwith thedataintheliterature,thisconfirmsandalsoextendsthe possibleroleofCEACAM1intumorgenerationaspresented inrecentreportsaboutCEACAM1asimportantregulatorof, presumablydifferentiation-dependent,apoptosis [12][13][14].For proliferation and apoptosis, we could not detect significant differencesbetweenthetumorentitiesanalyzedinourstudy ( fig.3). Thepvaluesofthe2-sidedWelcht-testforproliferationandapoptosiswerep=0.15andp=0.63,respectively.…”

“…The transmembrane glycoprotein CEACAM1 has been shown to be a regulator of tissue homeostasis through differentiation-dependent apoptosis in themilkductsofthehumanbreast [12]andalsoincoloncells [13,14].IthasbeenknownforyearsthatCEACAM1expres-sion is lost in the great majority of all colorectal neoplastic lesions [15,16].Morerecentstudieshavedemonstratedthat failuretoexpressCEACAM1duringcolonocytedifferentia-tion occurs very early in colon tumorigenesis and, interestingly, equally frequent in neoplastic and hyperplastic tumor lesions [12,13].Dysregulatedexpressionincolontumorshas also been described for other CEACAMs [15][16][17], although theirpatternsandfunctionsarelessclear.…”