Department of Surgery, Taitung MacKay Memorial Hospital, Taitung, Taiwan.
Department of Surgery, MacKay Memorial Hospital and MacKay Medical College, Taipei, Taiwan.
Endocrine. 2022 Oct;78(1):85-94. doi: 10.1007/s12020-022-03124-6. Epub 2022 Jun 27.
ATP-citrate lyase (ACLY) is a critical enzyme at the intersection of glucose and lipid metabolism. ACLY is often upregulated or activated in cancer cells to accelerate lipid synthesis and promote tumor progression. In this study, we aimed to explore the possibility of utilizing ACLY inhibition as a new strategy in the treatment of thyroid cancer.
Bioinformatics analysis of the public datasets was performed. Thyroid cancer cells were treated with two different ACLY inhibitors, SB-204990 and NDI-091143.
Bioinformatics analysis revealed that ACLY expression was increased in anaplastic thyroid cancer. In thyroid cancer cell lines FTC-133 and 8505C, ACLY inhibitors suppressed monolayer cell growth and clonogenic ability in a dose-dependent and time-dependent manner. Flow cytometry analysis showed that ACLY inhibitors increased the proportion of sub-G1 cells in the cell cycle and the number of annexin V-positive cells. Immunoblotting confirmed caspase-3 activation and PARP1 cleavage following treatment with ACLY inhibitors. Compromised cell viability could be partially rescued by co-treatment with the pan-caspase inhibitor Z-VAD-FMK. Additionally, we showed that ACLY inhibitors impeded three-dimensional growth and cell invasion in thyroid cancer cells. Isobolograms and combination index analysis indicated that ACLY inhibitors synergistically potentiated the cytotoxicity rendered by sorafenib.
Targeting ACLY holds the potential for being a novel therapeutic strategy for thyroid cancer.
三磷酸腺苷-柠檬酸裂解酶（ACLY）是糖代谢和脂代谢交汇的关键酶。在癌细胞中，ACLY 常被上调或激活，以加速脂质合成并促进肿瘤进展。在这项研究中，我们旨在探索抑制 ACLY 作为治疗甲状腺癌的新策略的可能性。
对公共数据集进行了生物信息学分析。用两种不同的 ACLY 抑制剂 SB-204990 和 NDI-091143 处理甲状腺癌细胞。
生物信息学分析显示，间变性甲状腺癌中 ACLY 的表达增加。在甲状腺癌细胞系 FTC-133 和 8505C 中，ACLY 抑制剂以剂量和时间依赖的方式抑制单层细胞生长和集落形成能力。流式细胞术分析显示，ACLY 抑制剂增加了细胞周期中 sub-G1 细胞的比例和膜联蛋白 V 阳性细胞的数量。免疫印迹证实 ACLY 抑制剂处理后 caspase-3 激活和 PARP1 裂解。用泛半胱天冬酶抑制剂 Z-VAD-FMK 共同处理可部分挽救细胞活力。此外，我们表明 ACLY 抑制剂阻碍了甲状腺癌细胞的三维生长和细胞侵袭。等效应图和组合指数分析表明，ACLY 抑制剂与索拉非尼协同增强了细胞毒性。
靶向 ACLY 可能成为治疗甲状腺癌的一种新的治疗策略。
