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

Abstract

BackgroundValproic 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.MethodsThe 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.ResultsThe 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).ConclusionVPA 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.

Knockdown delta-5-desaturase promotes the formation of a novel free radical byproduct from COX-catalyzed ω-6 peroxidation to induce apoptosis and sensitize pancreatic cancer cells to chemotherapy drugs

“…Considering that a variety of aliphatic acid compounds have been reported to inhibit histone deacetylase [54,55], we found that 8-HOA could also act as a histone deacetylase inhibitor (Fig. 1C).…”

Xanthohumol-Mediated Suppression of Notch1 Signaling Is Associated with Antitumor Activity in Human Pancreatic Cancer Cells

“…Various studies have suggested the involvement of multiple signaling pathways in the development, progression and metastasis of pancreatic cancer (30-37). One such pathway, Notch1 signaling, a highly conserved pathway throughout the animal kingdom, plays an important role in cellular differentiation, proliferation, and survival.…”

NKG2D and its ligands in cancer

“…DNA damage has been implicated in the induction of NKG2D ligands via DNA damage response ATM and ATR pathway [33]. Post-transcriptional epigenetic modifications with histone deacetylase (HDAC) inhibitors along with DNA damaging low-dose chemotherapy or radiotherapy can upregulate MICA/B expression in an array of human tumor cells [34,35 ●● ,36–39,40 ● ,41 ●● ]. Expression of MICA/B and ULBP3 can also be regulated by endogenous microRNAs [42–44].…”