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 suggested recently; however, the mechanism by which TG2 regulates apoptotic responses to
PDT remains to be elucidated. In this study, we investigated the key signaling pathways stimulated during apoptotic cell death following
PDT and whether inhibition of TG2 activation using pharmacological approaches and siRNAs 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
caspase-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 ΔΨ(m),
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.