JBC：发现癌症治疗中TG2促进细胞凋亡机制

Transglutaminase 2 promotes both caspase-dependent and -independent apoptotic cell death via the calpain/Bax signaling pathway

Je-Ok Yoo, Young-Cheol Lim, Young-Myeong Kim and Kwon-Soo Ha.

Transglutaminase 2 (TG2) is a versatile protein that is implicated in significant biological processes, including cell death and degenerative diseases. A possible role of TG2 in the apoptotic death of cancer cells induced by photodynamic therapy (PDT) was recently suggested;however, the mechanism by which TG2 regulates apoptotic responses to PDT remains to be elucidated. In the present study, we investigated the key signaling pathways stimulated during apoptotic cell death following PDT, and whether inhibition of TG2 activation using pharmacological approaches and small interfering RNAs affects the signaling pathways. PDT caused the release of both cytochrome c and apoptosis-inducing factor (AIF), by damaging mitochondria, which resulted in caspase-dependent and -independent apoptotic cell death, respectively.Released AIF translocated to the nucleus and, synergistically with the caspase-dependent pathway, led to apoptotic cell death. Both the caspase cascade and the activation of AIF following PDT were mediated by TG2 activation. In addition, PDT-activated calpain was responsible for the sequential events of Bax translocation, the collapse of the ΔΨm, caspase-3 activation, and AIF translocation, all of which were provoked by TG2 activation. Together, these results demonstrate that PDT with a chlorin-based photosensitizer targets TG2 by activating calpain-induced Bax translocation, which induces apoptotic cell death through both caspase-dependent and AIF-mediated pathways.Moreover, these results indicate that TG2 may be a possible therapeutic target for PDT treatment of cancer.