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Vanadyl bisacetylacetonate induced G1/S cell cycle arrest via high-intensity ERK phosphorylation in HepG2 cells

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Abstract

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 phophorylation 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 O2 •− nor H2O2 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.

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Abbreviations

DCFH-DA:

2,7-Dichlorofluorescein diacetate

ERK:

Extracellular signal-regulated protein kinase

FBS:

Fetal bovine serum

HE:

Dihydroethidium

JNK:

c-Jun N-terminal kinase

MAPK:

Mitogen-activated protein kinase

MEM:

Minimum essential medium

MTT:

3-(4,5-Dimethylthiazoyl-2-yl)-2,5-diphenyltetrazolium bromide

PBS:

Phosphate-buffered saline

PI3-K:

Phosphatidylinositol 3-kinase

pRb:

Retinoblastoma tumor suppressor protein

ROS:

Reactive oxygen species

Tris:

Tris(hydroxymethyl)aminomethane

[VO(acac)2]:

Vanadyl bisacetylacetonate

[VO(ma)2]:

Vanadyl bismaltolate

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (nos. 20637010 and 20671008) and by grants from the School of Pharmaceutical Sciences, Peking University.

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Authors and Affiliations

  1. Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, 100083, People’s Republic of China

    Ying Fu, Qin Wang, Xiao-Gai Yang, Xiao-Da Yang & Kui Wang

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  1. Ying Fu
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  2. Qin Wang
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  3. Xiao-Gai Yang
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Correspondence to Xiao-Gai Yang.

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Fu, Y., Wang, Q., Yang, XG. et al. Vanadyl bisacetylacetonate induced G1/S cell cycle arrest via high-intensity ERK phosphorylation in HepG2 cells. J Biol Inorg Chem 13, 1001–1009 (2008). https://doi.org/10.1007/s00775-008-0387-2

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