Increased Expression of Tissue Transglutaminase in Pancreatic Ductal Adenocarcinoma and Its Implications in Drug Resistance and Metastasis

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive neoplastic diseases and is virtually incurable. The molecular mechanisms that contribute to the intrinsic resistance of PDAC to various anticancer therapies are not well understood. Recently, we have observed that several drugresistant and metastatic tumors and tumor cell lines expressed elevated levels of tissue transglutaminase (TG2). Because PDAC exhibits inherent resistance to various drugs, we determined the constitutive expression of TG2 in 75 PDAC and 12 PDAC cell lines. Our results showed that 42 of 75 (56%) PDAC tumor samples expressed higher basal levels of TG2 compared with the normal pancreatic ducts [odds ratio (OR), 2.439; P = 0.012]. The increased expression of TG2 in PDAC was strongly associated with nodal metastasis (OR, 3.400; P = 0.017) and lymphovascular invasion (OR, 3.055; P = 0.045). Increased expression of TG2 was also evident in all 12 cell lines examined. The elevated expression of TG2 in PDAC cell lines was associated with gemcitabine resistance and increased invasive potential. Overexpression of catalytically active or inactive (C 277 S mutant) TG2 induced focal adhesion kinase (FAK) activation and augmented invasive functions in the BxPC-3 cell line. Conversely, down-regulation of TG2 by small interfering RNA attenuated FAK phosphorylation. Immunoprecipitation and confocal microscopy data revealed that TG2 was associated with FAK protein in PDAC cells. The activated FAK colocalized with TG2 at focal adhesion points. These results show for the first time that elevated expression of TG2 can induce constitutive activation of FAK and thus may contribute to the development of drug resistance and invasive phenotypes in PDAC. (Cancer Res 2006; 66(21): 10525-33)

Epidermal Growth Factor Receptor-mediated Tissue Transglutaminase Overexpression Couples Acquired Tumor Necrosis Factor-related Apoptosis-inducing Ligand Resistance and Migration through c-FLIP and MMP-9 Proteins in Lung Cancer Cells

“…It has been shown that TGM2 promotes cell growth, survival, and motility or invasion (38,39). Although increased TGM2 expression in cancer cells has been linked to increased drug resistance, metastasis, and poor patient survival (36,37,40), to our knowledge, this is the first report showing that TGM2 is overexpressed when acquired TRAIL resistance arises with the association of increased cell migration and invasion.…”

SUMOylation of Tissue Transglutaminase as Link between Oxidative Stress and Inflammation

“…Increased TG2 tissue levels have been observed in neurodegenerative diseases (28), including Alzheimer's, Huntington's, and Parkinson's diseases, as well as in chronic inflammatory conditions such as celiac disease (29). Increased tissue levels of TG2 have also been detected in cancer such as glioblastomas, malignant melanomas, and pancreatic ductal adenocarcinomas (30), and they are often associated with an increased metastatic activity or acquisition of drug resistance (30).…”

EGF potentiated oncogenesis requires a tissue transglutaminase-dependent signaling pathway leading to Src activation

“…Efforts to identify proteins in these breast-cancer cells, whose expression was up-regulated by EGF and therefore, potentially could contribute to its growth-promoting activity, led us to tTG, a dual-function enzyme that couples an ability to bind and hydrolyze GTP with a transamidation activity that cross-links proteins through glutamine-lysine or glutamine-polyamine linkages. Whereas there have been suggestions that chronic tTG expression and/or activation associated with some human cancers is linked to their malignant transformation (10)(11)(12)(13)(14)(15)(16), an understanding of how tTG is regulated in cancer cells and whether or not there is a functional relationship between this protein and EGFpromoted tumor growth has been lacking. Fig.…”