谷氨酰胺转移酶2(TG2)广泛存在许多重要的生命进程中,包括细胞死亡以及退化性疾病。光动力疗法(PDT)是癌症治疗的常用方法,但是它往往会引起正常细胞的凋亡。最近,韩国江原国立大学医学院的 Kwon-Soo Ha等人研究发现,TG2在这个过程可能扮演着重要角色。相关论文发表在3月14号的美国《生化周刊》(JBC)上。
一直以来,TG2调节细胞凋亡的机制还没有被阐明。在此次的研究中,研究人员研究了光动力疗法后与细胞凋亡有关的主要的信号通路。结果发现,不论是使用药理学方法或者是小干扰RNA来抑制TG2的活性都会影响这个信号通路。因为PDT通过损伤线粒体引起了细胞色素C以及凋亡诱导因子(AIF)的释放,结果导致了依赖caspase以及非依赖caspase的细胞凋亡。
释放后的AIF会转位到细胞核,与依赖caspase的信号通路协同作用,从而导致细胞凋亡。caspase级联反应以及光动力疗法后出现的AIF的激活,都会被激活的TG2所调停。除此之外,由PDT激活的钙蛋白酶会引起Bax转位的一系列进程。ΔΨm的衰竭,caspase-3的活化以及AIF的转位,都与TG2的活化有关。总而言之,这些结果证明了使用有光敏剂的PDT会通过激活钙蛋白酶引起的Bax转位来靶向作用于TG2,结果导致了通过依赖caspase以及AIF调节的信号通过引起的细胞凋亡。
此外,这些结果表明,TG2很可能会成为一个应对PDT的极佳治疗靶点。(生物谷Bioon.com)
doi: 10.1074/jbc.M111.326074
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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.