Reactive-oxygen-species-mediated Cdc25C degradation results in differential antiproliferative activities of vanadate, tungstate, and molybdate in the PC-3 human prostate cancer cell line.
The differential antiproliferative effects of vanadate, tungstate, and molybdate on human prostate cancer cell line PC-3 were compared and the underlying mechanisms were investigated. The results demonstrate that all of the three oxoanions can cause G(2)/M cell cycle arrest, which is evidenced by the increase in the level of phosphorylated Cdc2 at its inactive Tyr-15 site. Moreover, even if the difference in cellular uptake among the three oxoanions is excluded from the possible factors affecting their antiproliferative activity, vanadate exerted a much more potent effect in PC-3 cells than the other two oxoanions. Our results also reveal that reactive oxygen species (ROS)-mediated degradation of Cdc25C rather than Cdc25A or Cdc25B is responsible for vanadate-induced G(2)/M cell cycle arrest. We propose a possible mechanism to clarify the differential effect of the three oxoanions in biological systems beyond just considering that they are structural analogs of phosphate. We suggest that ROS formation is unlikely to be involved in the biological function of tungstate and molybdate, whereas the redox properties of vanadium may be important factors for it to exert pharmacological effects. Further, given the evidence from epidemiology studies of the association between diabetes and prostate cancer, the possibility of vanadate as a good candidate as both an antidiabetic and an anticancer agent or a chemopreventive agent is indicated.
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, People's Republic of China.
Tong-Tong
TT
Liu
Yan-Jun
YJ
Liu
Qin
Q
Wang
Xiao-Gai
XG
Yang
Kui
K
Wang
D000970:Antineoplastic Agents / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D006801:Humans; D008297:Male; D008982:Molybdenum / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy; D017382:Reactive Oxygen Species / Q000378:metabolism*; D017973:Tungsten Compounds / Q000494:pharmacology*; D014638:Vanadates / Q000494:pharmacology*; D020687:cdc25 Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D017973:Tungsten Compounds; C044659:molybdate; D014638:Vanadates; D008982:Molybdenum; D020687:cdc25 Phosphatases; C045951:tungstate