Antianoikis Effect of Nuclear Factor-κB through Up-regulated Expression of Osteoprotegerin, BCL-2, and IAP-1

Abstract

Contact with extracellular matrix provides survival signals to epithelial cells. When epithelial cells lose such contacts, a form of apoptosis results, which has been termed anoikis (1). Physiologically, anoikis is important in the regulation of cell number in the intestinal tract, where epithelial cells are shed from villus tips in the small intestine and from the intercrypt epithelium of the colon and die by anoikis (2, 3). Pathophysiologically, resistance to anoikis has been associated with metastatic spread of carcinoma cells (4, 5), which reflects the ability of malignantly transformed epithelial cells to evade apoptosis when deprived of extracellular matrix attachment during dissemination in lymph or blood. The molecular mechanisms that govern susceptibility to anoikis have not been fully characterized and could provide important insights into epithelial homeostasis and carcinogenesis.It was previously established that the survival of cells cultured without extracellular attachments is promoted by PI 3-K 2 and AKT because inhibition of these kinases increased anoikis (6, 7). Moreover, the anchorage-independent survival of cancer cells that is induced by transforming oncogenes such as Ras and Src depends in part on PI 3-K and AKT (8 -10). However, the molecular mechanisms by which cells activate PI 3-K and AKT after loss of extracellular attachments and through which this pathway blocks anoikis have not been completely characterized; nor have the molecular factors that ultimately control the susceptibility of cells to undergo anoikis been identified.NF-B constitutes a family of transcription factors defined by the presence of a Rel homology domain. When exposed to certain stresses, such as inflammation, infection, oxidative stress, or DNA double strand breaks, NF-B dissociates from inhibitory I B molecules, translocates from cytoplasm to nucleus, and binds to B sequences in the promoter regions of specific target genes, up-regulating their expression (11). Prominent among the more than 150 genes known to be regulated by NF-B proteins are a subset whose products inhibit apoptosis, including BCL-X L , BCL-2, IAP-1 and -2, c-FLICE inhibitory protein, growth arrest and DNA damage associated protein 45␤, and tumor necrosis factor (TNF) receptor-associated proteins 1 and 2 (12). NF-B activation is strongly associated with resistance to apoptosis induced by TNF-␣ (13), ionizing radiation (14), and cancer chemotherapeutic drugs (15). An important role for NF-B in carcinogenesis has been proposed, based on the oncogenicity of v-rel (16), the effect of NF-B in promoting chemotherapy and radiotherapy resistance of cancer cells (17), and the functional requirement for NF-B in tumorigenesis in the colon, breast, and liver (18 -20). Because of the importance of NF-B in apoptosis resistance and carcinogenesis, we suspected that this factor might regulate anoikis.To address this possibility, we evaluated a functional role for NF-B in the regulation of anoikis susceptibility, using a suspension culture model of intestinal e...

Detachment-induced upregulation of XIAP and cIAP2 delays anoikis of intestinal epithelial cells

“…In this regard, we established previously that detachmentinduced activation of NF-kB delays anoikis of nonmalignant rat intestinal epithelial cells IEC-18 (Yan et al, 2005). Recently, these results have been supported by findings, according to which detachment-induced activation of this transcription factor delays anoikis of non-malignant cells RIE-1, another cell line derived from rat intestinal epithelium (Toruner et al, 2006). In agreement with these two studies, we have observed that detachment-induced upregulation of XIAP and cIAP2 occurs both in IEC-18 and RIE-1 cells.…”

“…We found previously that detachment of IEC-18 cells results in the activation of the transcription factor NF-kB, an antiapoptotic event that noticeably delays anoikis of these cells (Yan et al, 2005). This role of NF-kB in detachment-induced apoptosis is not unique to IEC-18 cells as, according to a recent study, anoikis of non-malignant rat intestinal epithelial cells RIE-1, is also delayed by detachment-dependent activation of NF-kB (Toruner et al, 2006). Furthermore, XIAP and cIAP2 are well-established targets of NF-kB that were shown to be upregulated by this transcription factor in various cellular systems (Stehlik et al, 1998;Wang et al, 1998;Biswas et al, 2003).…”

MnSOD protects colorectal cancer cells from TRAIL-induced apoptosis by inhibition of Smac/DIABLO release

“…In colon cancer, as well as other tumor types, constitutively elevated levels of NF-kB have also been described (Wang et al, 1999;Smirnov et al, 2001) and recently, Toruner et al (2006) linked this phenotype to resistance to anoikis by increased expression of osteoprotegerin (OPG), which is a secreted and soluble TRAIL receptor. OPG can function as a decoy receptor or TRAIL and also block the tumor surveillance and antimetastasis activity of TRAIL.…”

Nitric Oxide Regulates Tumor Cell Cross-Talk with Stromal Cells in the Tumor Microenvironment of the Liver

“…18 Tumor cell suspension cultures were performed by plating cells in Petri dishes that had been previously coated with polyhydroxyethylmethacrylate (poly-HEMA). Poly-HEMA-coated dishes were prepared by two applications of a 10-mg/ml solution of poly-HEMA in 95% ethanol onto Petri dishes and washed three times with 1ϫ PBS before use.…”