Vanadyl bisacetylacetonate induced G1/S cell cycle arrest via high-intensity ERK phosphorylation in HepG2 cells.
In recent years the anticancer properties of vanadium compounds have been noticed, but the underlying mechanisms are not well understood. In the present work, we found that vanadyl bisacetylacetonate ([VO(acac)(2)]) blocked cell cycle progression permanently at G1 phase in a dose- and time-dependent manner in HepG2 cells. This was further evidenced by the growth regulatory signals during the G1 stage. After the treatment with [VO(acac)(2)], the level of phosphorylation of retinoblastoma tumor suppressor protein (pRb) and the expressions of cyclin D1, cyclin E and cyclin A were reduced, while the expression of a cyclin-dependent kinase inhibitor p21 was increased dose-dependently. In the meantime, neither O(2)(*-) nor H(2)O(2) level was observed to increase. Interestingly, the levels of phosphorylated extracellular signal-regulated protein kinase (ERK) and Akt were highly activated. After 1-h pretreatment with a lower concentration of MEK inhibitor U0126, the level of phosphorylated pRb was restored, indicating a release of cell cycle arrest. Taken together, we suggested that [VO(acac)(2)]-induced proliferation inhibition was caused by G1/S cell cycle arrest, which resulted from the decreased level of phosphorylated pRb in its active hypophosphorylated form via a highly activated ERK signal in HepG2 cells. The results presented here provided new insight into the development of vanadium compounds as potential anticancer agents.
Fu
Ying
Y
Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100083, People's Republic of China.
Wang
Qin
Q
Yang
Xiao-Gai
XG
Yang
Xiao-Da
XD
Wang
Kui
K
D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects* / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D006885:Hydroxybutyrates / Q000494:pharmacology*; D010422:Pentanones / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism; D016196:S Phase / Q000187:drug effects; D013997:Time Factors; D014638:Vanadates / Q000494:pharmacology
D006885:Hydroxybutyrates; D010422:Pentanones; C049529:acetyl acetonate; D014638:Vanadates; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases