The role of transglutaminase 2 in the radioresistance of melanoma cells

Transglutaminase 2 (TG2) is a protein expressed in many tissues that exerts numerous, some-times contradictory intra- and extracellular functions under both physiological and pathophysi-ological conditions. In the context of tumor progression, it has been found to be involved in cell adhesion, DNA repair mechanisms, the induction of apoptosis, and mesenchymal transdifferen-tiation, among others. Here, we hypothesized that TG2 also contributes to the radioresistance of two human melanoma cell lines A375 and MeWo which differ in their basal TG2 biosynthesis by examining their proliferation and clonal expansion after irradiation. For this purpose, cellular TG2 biosynthesis and TG2 activity were modulated by transfection-induced overexpression or TG2 knock-out and application of TG2-selective inhibitors. Proliferation and clonal expansion of TG2-overexpressing cells was not enhanced over wildtype cells, suggesting that increased TG2 biosynthesis does not further enhance the radioresistance of melanoma cells. Conversely, TG2 knock-out in A375 cells reduced their clonal and spheroidal expansion after irradiation, which indicates a contribution of TG2 to the radioresistance of melanoma cells. Since TG1, TG3, and partly also TG6 biosynthesis was detectable in A375 and MeWo cells, it can be assumed that these other members of the TG family may exert a partially compensatory effect.