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Bis(acetylacetonato)-oxidovanadium(IV) and sodium metavanadate inhibit cell proliferation via ROS-induced sustained MAPK/ERK activation but with elevated AKT activity in human pancreatic cancer AsPC-1 cells

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Abstract

In this study, the antiproliferative effect of bis(acetylacetonato)-oxidovanadium(IV) and sodium metavanadate and the underlying mechanisms were investigated in human pancreatic cancer cell line AsPC-1. The results showed that both exhibited an antiproliferative effect through inducing G2/M cell cycle arrest and can also cause elevation of reactive oxygen species (ROS) levels in cells. Moreover, the two vanadium compounds induced the activation of both PI3K/AKT and MAPK/ERK signaling pathways dose- and time-dependently, which could be counteracted with the antioxidant N-acetylcysteine. In the presence of MEK-1 inhibitor, the degradation of Cdc25C, inactivation of Cdc2 and accumulation of p21 were relieved. However, the treatment of AKT inhibitor did not cause any significant effect. Therefore, it demonstrated that the ROS-induced sustained MAPK/ERK activation rather than AKT contributed to vanadium compounds-induced G2/M cell cycle arrest. The current results also exhibited that the two vanadium compounds did not induce a sustained increase of ROS generation, but the level of ROS reached a plateau instead. The results revealed that an intracellular feedback loop may be against the elevated ROS level induced by vanadate or VO(acac)2, evidenced by the increased GSH content, the unchanged level at the expression of antioxidant enzymes. Therefore, vanadium compounds can be regarded as a novel type of anticancer drugs through the prolonged activation of MAPK/ERK pathway but retained AKT activity. The present results provided a proof-of-concept evidence that vanadium-based compounds may have the potential as both antidiabetic and antipancreatic cancer agents to prevent or treat patients suffering from both diseases.

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Abbreviations

BSA:

Bovine serum albumin

Cdc2:

Cell division control protein 2 homolog

CM-H2DCFDA:

5-(and-6)-Chloromethyl-2′,7′-dichlorodihydro-fluorescein diacetate

DMSO:

Dimethylsulfoxide

ERK:

Extracellular signal-regulated protein kinase

GSH:

Glutathione

MAPK:

Mitogen-activated protein kinase

MTT:

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

NAC:

N-acetyl cysteine

PI3K:

Phosphatidylinositol 3-kinase

PI:

Propidium iodide

ROS:

Reactive oxygen species

RNase A:

Ribonuclease A

SDS-PAGE:

Sodium dodecyl sulfate–polyacrylamide gel electrophoresis

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (21171011 and 21671009).

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Authors and Affiliations

  1. Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, People’s Republic of China

    Jing-Xuan Wu, Yi-Hua Hong & Xiao-Gai Yang

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  1. Jing-Xuan Wu
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Correspondence to Xiao-Gai Yang.

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Wu, JX., Hong, YH. & Yang, XG. Bis(acetylacetonato)-oxidovanadium(IV) and sodium metavanadate inhibit cell proliferation via ROS-induced sustained MAPK/ERK activation but with elevated AKT activity in human pancreatic cancer AsPC-1 cells. J Biol Inorg Chem 21, 919–929 (2016). https://doi.org/10.1007/s00775-016-1389-0

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