Transglutaminase 2 as a cisplatin resistance marker in non-small cell lung cancer

Abstract

We showed that good responders of cisplatin in NSCLC could be identified by the promoter methylation of TGM2 and that TGase 2 inhibition appears to be an effective cisplatin-sensitizing modality in NSCLC.

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.…”

Transglutaminase 2: A New Paradigm for NF‐κB Involvement in Disease

“…Recent studies have provided clues that TGase 2 expression can be induced by demethylation of certain regions in the promoter, which results in constitutive NF-B activation, contributing to drug resistance [12,13]. Maiuri et al showed that mutation of cystic fibrosis (CF) transmembrane conductance regulatory genes could cause TGase 2 activation via loss of ion transport, including calcium ions [14].…”

“…However, the stress adaptor molecules or signaling pathways involved in these responses are not clearly understood. Interestingly, we found that inhibition of TGase 2 using cystamine and R2 inhibitor in LPS-induced microglia dramatically decreased the expression of TGase 2 ( Figure 2 This vicious cycle must be controlled in normal conditions by sumoylation of I-B␣, which prevents I-B␣ polymerization by TGase 2 [22], or methylation of the TGase 2 promoter, which suppresses TGase 2 transcription [12,13,23]. Consistent with this hypothesis, in TGase 2-transfected cells, inflammatory stress results in a more dramatic increase in NF-B activation than in control cells [163].…”

“…Therefore, aberrant expression of TGase 2 contributes to the development of disease pathologies in cancers [4,141,142]. Recent studies have suggested that TGase 2 expression could be induced by demethylation of certain regions of the TGM2 promoter [12,13,23], which leads to constitutive NF-B activation associated with drug resistance in breast, ovarian, and lung cancers [24]. Cell lines with TGM2 promotermethylation, HCC-95 and HCC-1588, showed relatively higher sensitivity to cisplatin than TGM2-expressing cell lines (NCI-H1299 and HCC-1195).…”

Anti‐inflammatory effects of the R2 peptide, an inhibitor of transglutaminase 2, in a mouse model of allergic asthma, induced by ovalbumin

“…TGase 2 is aberrantly activated in tissues and cells and contributes to neurodegenerative diseases, such as Alzheimer's disease (Citron et al, 2001), Parkinson's disease (Junn et al, 2003;Andrings et al, 2004), neuro-AIDS (Roberts et al, 2003), Huntington's diseases (Kim et al, 2005), hippocampal CA 1 ischemia (Hwang et al, 2009), celiac disease (Naiyer et al, 2008), lupus (Sanchez et al, 2000), autoimmune diseases like rheumatic arthritis (Picarelli et al, 2003), human atherosclerotic coronary arteries (Cho et al, 2008), breast cancers (Park et al, 2009a) and drug resistance in variety of cancer cells Park et al, 2009bPark et al, , 2010. TGase 2 expression is increased in inflammatory diseases such as activation of microglia, a hallmark of brain inflammation (Park et al, 2004), idiopathic inflammatory myopathies (Kim, 2006) and allergic asthma (Hallstrand et al, 2010).…”