2. Academic Validation
  3. DHRS2-induced SPHK1 downregulation contributes to the cell growth inhibition by Trichothecin in colorectal carcinoma

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

  • Biochim Biophys Acta Mol Cell Res. 2024 Dec;1871(8):119846. doi: 10.1016/j.bbamcr.2024.119846.
Huiwen Liu 1,  Xiang Li 2,  Wenbin Liu 3,  Chunhong Zhang 1,  Shuzhao Zhang 1,  Xinran Zhou 4,  Ann M Bode 5,  Xiangjian Luo 6
Affiliations

Affiliations

  • 1 Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, PR China; NHC Key Laboratory of Carcinogenesis, the Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan 410078, PR China.
  • 2 Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan 410078, PR China.
  • 3 Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, PR China; Department of Pathology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, PR China.
  • 4 Hengyang Medical College, University of South China, Hengyang 421001 Hunan, PR China.
  • 5 The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
  • 6 Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, PR China; NHC Key Laboratory of Carcinogenesis, the Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan 410078, PR China; Key Laboratory of Biological Nanotechnology of National Health Commission, Central South University, Changsha, Hunan 410078, China. Electronic address: luocsu@csu.edu.cn.
PMID: 39284549 DOI: 10.1016/j.bbamcr.2024.119846
Abstract

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.

Keywords

Colorectal cancer; Dehydrogenase/reductase member 2; Sphingolipid metabolism; Sphingosine kinase 1; Trichothecin.

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