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Open Access Highly Accessed Research article

Valproic acid sensitizes pancreatic cancer cells to natural killer cell-mediated lysis by upregulating MICA and MICB via the PI3K/Akt signaling pathway

Pengfei Shi, Tao Yin, Feng Zhou, Pengfei Cui, Shanmiao Gou* and Chunyou Wang*

Author Affiliations

Pancreatic Disease Institute, Department of General Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei Province 430022, P. R. China

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BMC Cancer 2014, 14:370  doi:10.1186/1471-2407-14-370

Published: 25 May 2014

Abstract

Background

Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, is reported to exert anti-tumor effects by upregulating the expression of the natural killer group 2D (NKG2D) ligands on tumor cells; however, the mechanisms vary in different tumor types, and the effect and mechanism of action of VPA in pancreatic cancer cells are unknown.

Methods

The present study evaluated the effect of VPA to susceptibility of pancreatic cancer cells to the NK cell-mediated lysis in vitro and in vivo. Then we investigated the mechanism which the effect of VPA depend on.

Results

The lactate dehydrogenase assay (LDH) and xenograft experiment demonstrated that VPA significantly sensitized pancreatic cancer cells to NK cell-mediated lysis in vitro and in vivo. Quantitative real time- polymerase chain reaction (qRT-PCR) and flow cytometry demonstrated that VPA upregulated the mRNA and cell surface expression of the NKG2D ligands major histocompatibility complex class I-related chain A and B (MICA and MICB) in pancreatic cancer cells. Effects of VPA both in vitro and in vivo were significantly attenuated by the PI3K/Akt pathway inhibitor LY294002 or a siRNA targeting PI3K catalytic subunit alpha isoform (PI3KCA).

Conclusion

VPA enhances the susceptibility of pancreatic cancer cells to NK cell-mediated cytotoxicity both in vitro and in vivo by upregulating the expression of MICA and MICB via a PI3K/Akt signaling pathway-dependent mechanism.

Keywords:
Valproic acid; Pancreatic cancer; Natural killer cells; MICA and MICB; PI3KCA protein