Curcumin inhibits protein phosphatases 2A and 5, leading to activation of mitogen-activated protein kinases and death in tumor cells.
Curcumin can induce p53-independent apoptosis. However, the underlying mechanism remains to be defined. Here, we show that curcumin-induced apoptosis in a panel of tumor cells with mutant p53. Curcumin rapidly induced activation of the mitogen-activated protein kinases (MAPKs) including extracellular signal-regulated kinase 1/2 (Erk1/2) and c-Jun N-terminal kinase (JNK). Inhibition of JNK (with SP600125) or Erk1/2 (with U0126) partially prevented curcumin-induced cell death in the cells. Similarly, expression of dominant negative c-Jun or downregulation of Erk1/2 in part attenuated curcumin-induced cell death. It appears that curcumin-induced activation of MAPKs and apoptosis was due to induction of reactive oxygen species (ROS), as pretreatment with N-acetyl-L-cysteine, a ROS scavenger, blocked these events. Furthermore, we found that curcumin-induced activation of MAPK pathways was related to inhibition of the serine/threonine protein phosphatases 2A (PP2A) and 5 (PP5). Overexpression of PP2A or PP5 partially prevented curcumin-induced activation of JNK and Erk1/2 phosphorylation as well as cell death. The results suggest that curcumin induction of ROS activates MAPKs, at least partially by inhibiting PP2A and PP5, thereby leading to p53-independent apoptosis in tumor cells.
Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan 250012, Shandong Province, People's Republic of China.
Xiuzhen
X
Han
Baoshan
B
Xu
Christopher S
CS
Beevers
Yoshinobu
Y
Odaka
Long
L
Chen
Lei
L
Liu
Yan
Y
Luo
Hongyu
H
Zhou
Wenxing
W
Chen
Tao
T
Shen
Shile
S
Huang
D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D003474:Curcumin / Q000494:pharmacology*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors*; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D009687:Nuclear Proteins; D020928:Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; C089641:protein phosphatase 5; D003474:Curcumin