Valproic acid sensitizes pancreatic cancer cells to natural killer cell-mediated lysis by upregulating MICA and MICB via the PI3K/Akt signaling pathway.
Valproic acid sensitizes pancreatic cancer cells to natural killer cell-mediated lysis by upregulating MICA and MICB via the PI3K/Akt signaling pathway.
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丙戊酸通过通过PI3K/AKT信号通路上调云母和MICB，使胰腺癌细胞对天然杀伤细胞介导的裂解敏感。
DOI：
10.1186/1471-2407-14-370
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发表时间：
2014-05-25
期刊：
影响因子：
3.8
通讯作者：
Wang C
中科院分区：
文献类型：
--
作者：
Shi P;Yin T;Zhou F;Cui P;Gou S;Wang C
据报道，丙戊酸（VPA）是一种组蛋白脱乙酰酶（HDAC）抑制剂，通过上调肿瘤细胞上自然杀伤组2D（NKG 2D）配体的表达发挥抗肿瘤作用;然而，不同肿瘤类型的机制不同，VPA在胰腺癌细胞中的作用和作用机制尚不清楚。本研究在体外和体内评价VPA对胰腺癌细胞对NK细胞介导的裂解的易感性的影响。乳酸脱氢酶（LDH）测定和异种移植实验表明，VPA在体内外均能显著增强胰腺癌细胞对NK细胞的杀伤作用。定量真实的时间聚合酶链反应（qRT-PCR）和流式细胞术证实，VPA上调胰腺癌细胞中NKG 2D配体主要组织相容性复合物I类相关链A和B（云母和MIC B）的mRNA和细胞表面表达。VPA在体外和体内的作用均被PI 3 K/Akt通路抑制剂LY 294002或靶向PI 3 K催化亚基α亚型（PI 3 KCA）的siRNA显著减弱。VPA通过PI 3 K/Akt信号通路依赖性机制上调云母和MICB的表达，增强胰腺癌细胞对NK细胞介导的细胞毒性的体外和体内易感性。
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. 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. 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). 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.
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