DHRS2-诱导的SPHK1下调是单端孢霉烯抑制结直肠癌细胞生长的原因。

IF 4.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research Pub Date : 2024-09-14 DOI:10.1016/j.bbamcr.2024.119846

Huiwen Liu , Xiang Li , Wenbin Liu , Chunhong Zhang , Shuzhao Zhang , Xinran Zhou , Ann M. Bode , Xiangjian Luo

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引用次数: 0

摘要

背景：脂质代谢失调是癌症最突出的代谢特征之一。鞘脂代谢途径的激活会影响肿瘤（包括结直肠癌）的增殖、侵袭、血管生成、化疗抵抗和免疫逃逸。据报道，属于短链脱氢酶/还原酶（SDR）家族的脱氢酶/还原酶成员 2（DHRS2）参与调控脂质代谢并影响癌症进展。单端孢霉烯（TCN）是一种倍半萜类代谢物，来源于草本植物 Maytenus hookeri Loes 的一种内生真菌。研究表明，TCN 具有广谱抗肿瘤活性：方法：我们通过 CCK8 和集落形成试验评估了 CRC 细胞的增殖能力。采用液相色谱-质谱联用技术（LC/MS）进行代谢物分析，以确定与 DHRS2 过表达相关的近端代谢物变化。我们采用 RNA 稳定性分析和 RNA 免疫沉淀（RIP）实验来确定 DHRS2 对 SPHK1 表达的转录后调控。我们使用流式细胞术检测了在 TCN 缺失或存在的情况下 CRC 细胞周期和细胞凋亡的变化：结果：我们证明，DHRS2阻碍了鞘氨醇激酶1（SPHK1）/1-磷酸鞘氨醇（S1P）代谢途径，从而抑制了CRC细胞的生长。DHRS2 直接与 SPHK1 mRNA 结合，以转录后调控的方式加速其降解。此外，我们还发现 DHRS2 诱导的 SPHK1 下调有助于 TCN 诱导的 CRC 生长抑制：本研究提供了代谢酶、代谢产物与 CRC 恶性进展之间的机理联系。此外，通过诱导 DHRS2 和靶向 SPHK1/S1P 代谢途径，TCN 可被开发为一种潜在的抗肿瘤药物。

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DHRS2-induced SPHK1 downregulation contributes to the cell growth inhibition by Trichothecin in colorectal carcinoma

Background

Deregulation of lipid metabolism is one of the most prominent metabolic features in cancer. The activation of sphingolipid metabolic pathways affects the proliferation, invasion, angiogenesis, chemoresistance, and immune escape of tumors, including colorectal cancer (CRC). Dehydrogenase/reductase member 2 (DHRS2), which belongs to the short-chain dehydrogenase/reductase (SDR) family, has been reported to participate in the regulation of lipid metabolism and impact on cancer progression.

Trichothecin (TCN) is a sesquiterpenoid metabolite originating from an endophytic fungus of the herbal plant Maytenus hookeri Loes. Studies have shown that TCN exerts a broad-spectrum antitumor activity.

Methods

We evaluated the proliferative ability of CRC cells by CCK8 and colony formation assays. A metabolite profiling using liquid chromatography coupled with mass spectrometry (LC/MS) was adopted to identify the proximal metabolite changes linked to DHRS2 overexpression. RNA stability assay and RNA immunoprecipitation (RIP) experiments were applied to determine the post-transcriptional regulation of SPHK1 expression by DHRS2. We used flow cytometry to detect changes in cell cycle and cell apoptosis of CRC cells in the absence or presence of TCN.

Results

We demonstrate that DHRS2 hampers the sphingosine kinases 1 (SPHK1)/sphingosine 1-phosphate (S1P) metabolic pathway to inhibit CRC cell growth. DHRS2 directly binds to SPHK1 mRNA to accelerate its degradation in a post-transcriptionally regulatory manner. Moreover, we illustrate that SPHK1 downregulation induced by DHRS2 contributes to TCN-induced growth inhibition of CRC.

Conclusions

The present study provides a mechanistic connection among metabolic enzymes, metabolites, and the malignant progression of CRC. Moreover, TCN could be developed as a potential pharmacological tool against CRC by the induction of DHRS2 and targeting SPHK1/S1P metabolic pathway.

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来源期刊

Biochimica et biophysica acta. Molecular cell research 生物-生化与分子生物学

CiteScore

10.00

自引率

2.00%

发文量

151

审稿时长

44 days

期刊介绍： BBA Molecular Cell Research focuses on understanding the mechanisms of cellular processes at the molecular level. These include aspects of cellular signaling, signal transduction, cell cycle, apoptosis, intracellular trafficking, secretory and endocytic pathways, biogenesis of cell organelles, cytoskeletal structures, cellular interactions, cell/tissue differentiation and cellular enzymology. Also included are studies at the interface between Cell Biology and Biophysics which apply for example novel imaging methods for characterizing cellular processes.