Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, 150 Ji-Mo Rd, Shanghai, 200120, China.
Department of Colorectal Surgery, Department of General Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.
Pharm Res. 2022 May;39(5):867-876. doi: 10.1007/s11095-022-03291-1. Epub 2022 May 16.
Gastric cancer (GC) remains a significant health problem and carries with it substantial morbidity and mortality. Chidamide is a novel and orally administered histone deacetylase (HDAC) inhibitor and has been demonstrated its anti-tumor efficacy on different kinds of hematological and solid tumors. However, the underlying mechanism of chidamide resistance is still poorly characterized.
We established chidamide resistant GC cell lines, AGS ChiR and MGC803 ChiR and investigated the toxicologic effects through cell survival, colony formation and flow cytometry assays in vitro, and a subcutaneous xenograft model in vivo. RNA-sequence was then performed to screen chidamide resistance-associated genes between AGS and AGS ChiR cells. The role of Lymphocyte cytosolic protein 1 (LCP1) in chidamide resistance was explored by gain- and loss-of-function analyses.
We found that chidamide significantly inhibited cell proliferation and induced the apoptosis in a concentration-dependent manner in wild-type GC cell lines as compared to chidamide resistant cell lines. The transcriptomic profiling, quantitative RT-PCR, and western blot data revealed that LCP1 was upregulated in AGS ChiR cells compared with parental cells. Overexpression of LCP1 conferred and knockdown of LCP1 attenuated the chidamide resistance of GC cells. Epigenetic derepression of LCP1 by chidamide may be a possible reason for the contribution of LCP1 to chidamide resistance.
These findings illustrated that LCP1 may play a chidamide resistance role in GC, suggesting that LCP1 could be a potential target for the therapy of GC combined with chidamide.
胃癌（GC）仍然是一个重大的健康问题，其发病率和死亡率都很高。西达本胺是一种新型的口服组蛋白去乙酰化酶（HDAC）抑制剂，已在多种血液系统和实体肿瘤中显示出其抗肿瘤疗效。然而，西达本胺耐药的潜在机制仍知之甚少。
我们建立了西达本胺耐药的 GC 细胞系 AGS ChiR 和 MGC803 ChiR，并通过体外细胞存活、集落形成和流式细胞术检测以及皮下异种移植模型研究了其毒理学效应。然后通过 RNA 测序筛选 AGS 和 AGS ChiR 细胞之间与西达本胺耐药相关的基因。通过功能获得和功能丧失分析探讨淋巴细胞胞质蛋白 1（LCP1）在西达本胺耐药中的作用。
与耐药细胞系相比，西达本胺在野生型 GC 细胞系中以浓度依赖性方式显著抑制细胞增殖并诱导细胞凋亡。转录组谱、定量 RT-PCR 和 Western blot 数据显示，与亲本细胞相比，AGS ChiR 细胞中 LCP1 上调。LCP1 的过表达赋予了 GC 细胞对西达本胺的耐药性，而 LCP1 的敲低则减弱了 GC 细胞对西达本胺的耐药性。西达本胺对 LCP1 的表观遗传去抑制可能是 LCP1 对西达本胺耐药的原因之一。
这些发现表明 LCP1 可能在 GC 中发挥西达本胺耐药作用，提示 LCP1 可能成为 GC 联合西达本胺治疗的潜在靶点。
