Overexpression of Tissue Transglutaminase Leads to Constitutive Activation of Nuclear Factor-κB in Cancer Cells: Delineation of a Novel Pathway

Abstract

The transcription factor nuclear factor-KB (NF-KB) plays an important role in regulating cell growth, apoptosis, and metastatic functions. Constitutive activation of NF-KB has been observed in various cancers; however, molecular mechanisms resulting in such activation remain elusive. Based on our previous results showing that drug-resistant and metastatic cancer cells have high levels of tissue transglutaminase (TG2) expression and that this expression can confer chemoresistance to certain types of cancer cells, we hypothesized that TG2 contributes to constitutive activation of NF-KB. Numerous lines of evidence showed that overexpression of TG2 is linked with constitutive activation of NF-KB. Tumor cells with overexpression of TG2 exhibited increased levels of constitutively active NF-KB. Activation of TG2 led to activation of NF-KB; conversely, inhibition of TG2 activity inhibited activation of NF-KB. Similarly, ectopic expression of TG2 caused activation of NF-KB, and inhibition of expression of TG2 by small interfering RNA abolished the activation of NF-KB. Our results further indicated that constitutive NF-KB reporter activity in pancreatic cancer cells is not affected by dominant-negative IKBA. Additionally, coimmunoprecipitation and confocal microscopy showed that IKBA is physically associated with TG2. Lastly, immunohistochemical analysis of pancreatic ductal carcinoma samples obtained from 61 patients further supported a strong correlation between TG2 expression and NF-KB activation/overexpression (P = 0.0098, Fisher's exact test). We conclude that TG2 induces constitutive activation of NF-KB in tumor cells via a novel pathway that is most likely independent of IKBA kinase. Therefore, TG2 may be an attractive alternate target for inhibiting constitutive NF-KB activation and rendering cancer cells sensitive to anticancer therapies. (Cancer Res 2006; 66(17): 8788-95)

Transglutaminase Type II Is Involved in the Pathogenesis of Endotoxic Shock

“…On the contrary, in WT, the increased expression of TG2 induced by LPS might cause a continuous activation cycle in the inflammation process. Similarly, it has been reported that overexpression of TG2 in cancer cells induces constitutive activation of NF-B (44).…”

NF-κB and STAT3 signaling pathways collaboratively link inflammation to cancer

“…NF-kappa B (NF-κB) or Rel proteins comprise a family of Protein Cell & tence of NF-κB in the nucleus, is shown in a wide variety of tumor types, such as lymphoma, liver cancer, lung cancer, breast cancer, etc (Mann et al, 2006;Qiao et al, 2006;Baby et al, 2007;Lenz et al, 2008). Besides, NF-κB is activated in response to tobacco, stress, dietary agents, obesity, alcohol, infectious agents, irradiation, and environmental stimuli that commonly contribute to carcinogenesis.…”

Tissue transglutaminase links TGF-β, epithelial to mesenchymal transition and a stem cell phenotype in ovarian cancer

“…By using specific silencing or overexpression of TAK1 targets, we demonstrate that the main TG2 regulator in the non-canonical pathway is the NF-kB complex. As TG2 is a known inducer of NF-KB activity in OC (Cao et al, 2008) and in other cancer cells (Mann et al, 2006), it appears that a forward positive feed loop exists between the enzyme and NF-kB.…”

“…Tissue transglutaminase (TG2), an enzyme overexpressed in epithelial malignancies (Mann et al, 2006;Satpathy et al, 2007), participates in Ca þ þ -dependent protein post-translational modifications and cross-linking by transferring acyl groups between glutamine and lysine residues (Pincus and Waelsch, 1968). We reported that TG2 is upregulated in ovarian tumors Satpathy et al, 2007) and has a critical role in the process of epithelial-to-mesenchymal transition (EMT), a hallmark of cancer progression.…”