Transglutaminase 2 Promotes Migration and Invasion of Lung Cancer Cells

Abstract

Lung cancer is the leading cause of cancer deaths worldwide. Given that the major threat of cancer is metastasis, delineation of the molecular mechanism underlying it would help devise therapeutic strategies. Transglutaminase 2 (TG2), belonging to the transglutaminase superfamily, is a versatile protein with enzymatic and nonenzymatic functions. It mainly localizes inside the cell, but also appears extracellularly. Recent findings have demonstrated the involvement of TG2 in cancer development. Here we examine the role of TG2 in metastasis of lung cancer using a lung cancer cell line CL1-0, which exhibits low invasiveness, and its invasive subline CL1-5. Our results show that CL1-5 cells express a higher amount of TG2 than CL1-0 cells. Overexpression of TG2 in CL1-0 enhances cell migration and invasion, and lowering TG2 expression in CL1-5 cells reduces their ability to do so. The transamidase activity of TG2 is not required since cells expressing the inactive TG2 mutant or treated with a TG2 inhibitor are still able to migrate and invade. TG2-stimulated migration and invasion are, at least in part, mediated by Rac, as inhibition of Rac activity suppresses cell migration and invasion. Lastly, exogenous application of recombinant TG2 protein to CL1-0 cells substantially augments cell migration and invasion, suggesting the significance of extracellular TG2 in promoting these events. Collectively, our results show that TG2 plays a positive role in cell migration and invasion, and this might help metastasis of lung cancer cells.

Comprehensive analysis of tumor microenvironment and identification of an immune signature to predict the prognosis and immunotherapeutic response in lung squamous cell carcinoma

“…Transglutaminase 2 (TGM2) exerts multiple physiological functions and is associated with cancer cell survival and metastatic behavior (36). It has been reported that TGM2 promotes the migration and invasion of lung cancer cells (37). The expression of PTGIS was found to be correlated with lung cancer patient survival (38).…”

Inhibiting TG2 sensitizes lung cancer to radiotherapy through interfering TOPOIIα-mediated DNA repair

“…On normal status, TG2 is predominantly located in cytoplasm, even there is some located in the nucleus, the mitochondria, on the plasma membrane, or in the extracellular cell surface (31, 32). Extracellular TG2 is mainly involved in wound healing and scarring, tissue fibrosis and cancer metastasis (33).…”

Protein Promiscuity in H2O2Signaling

“…In this study, we hope to have emphasized that statement and encouraged consideration of moonlighting redox-regulated proteins as key players in deciding cellular fate under oxidative stress. CypA, TG2, CLIC (mentioned within the Transglutaminase 2 section), and DJ-1 are all associated with increased invasion and metastasis of cancer cells (133,138,197,422), with both DJ-1 and CypA exerting their influence through the regulation of kinase pathways (133,422). As cancer cells tend to block mitochondrial apoptotic induction, developments in cancer therapeutics often target the mitochondrial apoptosis signaling pathway, for example at p53 or the mPTP (105), and a direct link has been established between redox regulation of p53 and tumor progression (323).…”