Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Radiology, Xiangya Hospital, Central South University, Changsha, Hunan, 410078, People's Republic of China.
Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan, 410078, People's Republic of China.
J Exp Clin Cancer Res. 2019 Jul 10;38(1):300. doi: 10.1186/s13046-019-1301-1.
Cancer is fundamentally a deregulation of cell growth and proliferation. Cancer cells often have perturbed metabolism that leads to the alteration of metabolic intermediates. Dehydrogenase/reductase member 2 (DHRS2) belongs to short-chain alcohol dehydrogenase/reductase (SDR) superfamily, which is functionally involved in a number of intermediary metabolic processes and in the metabolism of lipid signaling molecules. DHRS2 displays closely association with the inhibition of cell proliferation, migration and quiescence in cancers.
3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4- sulfophenyl)-2H-tetrazolium (MTS), 5-ethynyl-2'-deoxyuridine (EdU) and colony formation assays were applied to evaluate the proliferative ability of nasopharyngeal carcinoma (NPC) cells. We performed lipid metabolite profiling using gas chromatography coupled with mass spectrometry (GC/MS) to identify the proximal metabolite changes linked to DHRS2 overexpression. RNA sequencing technique combined with differentially expressed genes analysis was applied to identify the expression of genes responsible for the anti-tumor effect of trichothecin (TCN), a natural sesquiterpenoid compound isolated from an endophytic fungus.
Our current findings reveal that DHRS2 affects lipid metabolite profiling to induce cell cycle arrest and growth inhibition in NPC cells. Furthermore, we demonstrate that TCN is able to induce growth inhibition of NPC in vitro and in vivo by up-regulating DHRS2.
Our report suggests that activating DHRS2 to reprogram lipid homeostasis may be a target for the development of targeted therapies against NPC. Moreover, TCN could be exploited for therapeutic gain against NPC by targeting DHRS2 and it may also be developed as a tool to enhance understanding the biological function of DHRS2.
癌症从根本上说是细胞生长和增殖的失调。癌细胞的代谢常常失调，导致代谢中间产物的改变。脱氢酶/还原酶成员 2（DHRS2）属于短链醇脱氢酶/还原酶（SDR）超家族，该酶在许多中间代谢过程和脂质信号分子的代谢中具有功能。DHRS2 与癌症中细胞增殖、迁移和静止的抑制密切相关。
采用 3-(4,5-二甲基噻唑-2-基）-5-(3-羧甲氧基苯基）-2-(4-磺基苯基）-2H-四唑（MTS）、5-乙炔基-2'-脱氧尿苷（EdU）和集落形成实验评估鼻咽癌（NPC）细胞的增殖能力。我们使用气相色谱-质谱联用（GC/MS）进行脂质代谢物谱分析，以鉴定与 DHRS2 过表达相关的近端代谢物变化。应用 RNA 测序技术结合差异表达基因分析，鉴定天然倍半萜化合物曲古抑菌素（TCN）抗肿瘤作用相关基因的表达，TCN 是从一种内生真菌中分离得到的。
我们目前的研究结果表明，DHRS2 影响脂质代谢物谱，诱导 NPC 细胞周期停滞和生长抑制。此外，我们证明 TCN 通过上调 DHRS2 能够在体外和体内诱导 NPC 的生长抑制。
我们的报告表明，激活 DHRS2 以重新编程脂质稳态可能是开发针对 NPC 的靶向治疗的一个靶点。此外，通过靶向 DHRS2，TCN 可用于治疗 NPC 并获得收益，也可能被开发为增强对 DHRS2 生物学功能理解的工具。
