, Volume 18, Issue 4, pp 435–451 | Cite as

Calpain, Atg5 and Bak play important roles in the crosstalk between apoptosis and autophagy induced by influx of extracellular calcium

  • Mei Shi
  • Tian Zhang
  • Lei Sun
  • Yan Luo
  • De-Hua Liu
  • Shu-Tao Xie
  • Xiao-Yan Song
  • Guo-Fan Wang
  • Xiu-Lan Chen
  • Bai-Cheng Zhou
  • Yu-Zhong Zhang
Original Paper


Calcium (Ca2+) signals are involved in important checkpoints in cell death pathways and promote both apoptosis and autophagy. However, the relationship between autophagy and apoptosis in response to Ca2+ level elevation is poorly understood. Here, we provided evidence that the influx of extracellular Ca2+ triggered by Trichokonin VI (TK VI), an antimicrobial peptide, induced calpain-dependent apoptosis and autophagy in hepatocellular carcinoma (HCC) cells. Remarkably, TK VI preferentially induced apoptosis that was associated with calpain-mediated Bax and Atg5 cleavage, which resulted in the collapse of the mitochondrial membrane potential and cytochrome c release. Interestingly, truncated, but not full-length Atg5, associated with Bcl-xL and promoted the intrinsic pathway. Moreover, TK VI treatment induced reactive oxygen species (ROS) accumulation, an effect in which Bak might play a major role. This accumulation of ROS resulted in the subsequent disposal of damaged mitochondria within autophagosomes via Atg5-mediated and mitochondria-selective autophagy. Both the inhibition of calpain activity and Bax deficiency activated a switch that promoted an enhancement of autophagy. The inhibition of both apoptosis and autophagy significantly attenuated the TK VI cytotoxicity, indicating that the two processes had stimulatory effects during TK VI-meditated cell death. These results suggested that calpain, Bak and Atg5 were molecular links between autophagy and apoptosis and revealed novel aspects of the crosstalk between these two processes. The potential of TK VI is proposed as a promising anticancer agent for its well-characterized activity of Ca2+ agonist and as a possible novel therapeutic strategy that acts on cancer cell mitochondria.


Calpain Atg5 Bak Apoptosis Autophagy Reactive oxygen species 


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Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Mei Shi
    • 1
  • Tian Zhang
    • 1
  • Lei Sun
    • 2
  • Yan Luo
    • 1
  • De-Hua Liu
    • 1
  • Shu-Tao Xie
    • 1
  • Xiao-Yan Song
    • 1
  • Guo-Fan Wang
    • 3
  • Xiu-Lan Chen
    • 1
  • Bai-Cheng Zhou
    • 1
  • Yu-Zhong Zhang
    • 1
  1. 1.Marine Biotechnology Research Center, State Key Laboratory of Microbial TechnologyShandong UniversityJinanPeople’s Republic of China
  2. 2.Biological Imaging CenterInstitute of Biophysics, Chinese Academy of SciencesBeijingPeople’s Republic of China
  3. 3.Shandong Cancer HospitalJinanPeople’s Republic of China

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