Vitamin K2 Induces Mitochondria-Related Apoptosis in Human Bladder Cancer Cells via ROS and JNK/p38 MAPK Signal Pathways

PLoS One. 2016 Aug 29;11(8):e0161886. doi: 10.1371/journal.pone.0161886. eCollection 2016.


The effects of vitamin K2 on apoptosis in a variety of cancer cells have been well established in previous studies. However, the apoptotic effect of vitamin K2 on bladder cancer cells has not been evaluated. The aim of this study is to examine the apoptotic activity of Vitamin K2 in bladder cancer cells and investigate the underlying mechanism. In this study, Vitamin K2 induced apoptosis in bladder cancer cells through mitochondria pathway including loss of mitochondria membrane potential, cytochrome C release and caspase-3 cascade. Furthermore, the phosphorylation of c-Jun N-terminal kinase (JNK) and p38 MAPK was detected in Vitamin K2-treated cells and both SP600125 (an inhibitor of JNK) and SB203580 (an inhibitor of p38 MAPK) completely abolished the Vitamin K2-induced apoptosis and loss of mitochondria membrane potential. Moreover, the generation of reactive oxygen species (ROS) was detected in bladder cancer cells, upon treatment of vitamin K2 and the anti-oxidant N-acetyl cysteine (NAC) almost blocked the Vitamin K2-triggered apoptosis, loss of mitochondria membrane potential and activation of JNK and p38 MAPK. Taken together, these findings revealed that Vitamin K2 induces apoptosis in bladder cancer cells via ROS-mediated JNK/p38 MAPK and Mitochondrial pathways.

MeSH terms

  • Anthracenes / pharmacology
  • Apoptosis / drug effects*
  • Cell Line, Tumor
  • Humans
  • Imidazoles / pharmacology
  • JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Membrane Potential, Mitochondrial / drug effects
  • Mitochondria / metabolism*
  • Phosphorylation / drug effects
  • Pyridines / pharmacology
  • Reactive Oxygen Species / metabolism
  • Urinary Bladder Neoplasms / metabolism
  • Vitamin K 2 / pharmacology*
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Anthracenes
  • Imidazoles
  • Pyridines
  • Reactive Oxygen Species
  • Vitamin K 2
  • pyrazolanthrone
  • JNK Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • SB 203580

Grants and funding

This work was supported by contract grant sponsor: NSFC (P.R. China), contract grant number 30971608; and contract grant sponsor NSF of the Hubei Province, contract grant number 2009CDB074.