通过抑制组蛋白去乙酰化酶 6 抑制 GRP78 向细胞表面易位可抑制胆管癌细胞的增殖。
Blockade of GRP78 Translocation to the Cell Surface by HDAC6 Inhibition Suppresses Proliferation of Cholangiocarcinoma Cells.
机构信息
Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea.
Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
出版信息
Anticancer Res. 2022 Jan;42(1):471-482. doi: 10.21873/anticanres.15505.
BACKGROUND/AIM: HDAC6, a cytoplasmic localized deacetylase, is a positive regulator of cancer progression via modification of various substrates. We evaluated how the interaction between HDAC6 and glucose regulatory protein 78 (GRP78) affects the growth of cholangiocarcinoma (CCA).
MATERIALS AND METHODS
The anti-tumor effects of ACY-1215, an HDAC6 specific inhibitor, in CCA cell lines were analyzed by cell viability assay, western blotting, flow cytometry, co-immunoprecipitation, and biotinylation assays. In vivo effects of ACY-1215 were evaluated in a xenograft model using CCA cell line TFK-1.
RESULTS
ACY-1215 increased the acetyl-form of GRP78 by approximately 50% compared to control, which impaired the translocation of GRP78 to the plasma membrane by 50% through alteration of cellular proliferative signaling via PI3K/AKT. Furthermore, ACY-1215 suppressed tumor growth by 50% compared to vehicle control in a CCA xenograft model.
CONCLUSION
Increase in GRP78 acetylation by HDAC6 inhibition suppressed GRP78 translocation to the cell surface, which inhibited proliferation and promoted apoptosis in CCA.
背景/目的：HDAC6 是一种细胞质定位的去乙酰化酶，通过修饰各种底物成为癌症进展的正调控因子。我们评估了 HDAC6 与葡萄糖调节蛋白 78（GRP78）之间的相互作用如何影响胆管癌（CCA）的生长。
材料和方法
通过细胞活力测定、western blot、流式细胞术、共免疫沉淀和生物素化分析，分析了 HDAC6 特异性抑制剂 ACY-1215 在 CCA 细胞系中的抗肿瘤作用。使用 CCA 细胞系 TFK-1 在异种移植模型中评估了 ACY-1215 的体内作用。
结果
与对照组相比，ACY-1215 使 GRP78 的乙酰化形式增加了约 50%，通过改变 PI3K/AKT 细胞增殖信号，使 GRP78 向质膜的易位减少了 50%。此外，与对照组相比，ACY-1215 在 CCA 异种移植模型中使肿瘤生长减少了 50%。
结论
HDAC6 抑制导致 GRP78 乙酰化增加，抑制了 GRP78 向细胞表面的易位，从而抑制了 CCA 的增殖并促进了细胞凋亡。
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