2. Academic Validation
  3. 13-Oxyingenol-dodecanoate inhibits the growth of non-small cell lung cancer cells by targeting ULK1

13-Oxyingenol-dodecanoate inhibits the growth of non-small cell lung cancer cells by targeting ULK1

  • Bioorg Chem. 2024 Apr 15:147:107367. doi: 10.1016/j.bioorg.2024.107367.
Xin-Ye Wang 1,  Yu-Jue Wang 1,  Bo-Wen Guo 1,  Zi-Lin Hou 1,  Gu-Xue Zhang 1,  Zheng Han 1,  Qingbo Liu 1,  Guo-Dong Yao 2,  Shao-Jiang Song 3
Affiliations

Affiliations

  • 1 Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning Province, Engineering Research Center of Natural Medicine Active Molecule Research & Development, Liaoning Province, Key Laboratory of Natural Bioactive Compounds Discovery & Modification, Shenyang, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China.
  • 2 Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning Province, Engineering Research Center of Natural Medicine Active Molecule Research & Development, Liaoning Province, Key Laboratory of Natural Bioactive Compounds Discovery & Modification, Shenyang, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China. Electronic address: guodong_yao@126.com.
  • 3 Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning Province, Engineering Research Center of Natural Medicine Active Molecule Research & Development, Liaoning Province, Key Laboratory of Natural Bioactive Compounds Discovery & Modification, Shenyang, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China. Electronic address: songsj99@163.com.
PMID: 38626492 DOI: 10.1016/j.bioorg.2024.107367
Abstract

Lung Cancer is the leading cause of Cancer deaths worldwide. Non-small cell lung Cancer (NSCLC) accounts for 80-85% of all lung cancers. Euphorbia kansui yielded 13-oxyingenol-dodecanoate (13OD), an ingenane-type diterpenoid, which had a strong cytotoxic effect on NSCLC cells. The underlying mechanism and potential target, however, remained unknown. The study found that 13OD effectively inhibited the cell proliferation and colony formation of NSCLC cells (A549 and H460 cells), with less toxicity in normal human lung epithelial BEAS-2B cells. Moreover, 13OD can cause mitochondrial dysfunction, and Apoptosis in NSCLC cells. Mechanistically, the transcriptomics results showed that differential genes were mainly enriched in the mTOR and AMPK signaling pathways, which are closely related to cellular Autophagy, the related indicators were subsequently validated. Additionally, bafilomycin A1 (Baf A1), an Autophagy Inhibitor, reversed the mitochondrial damage caused by 13OD. Furthermore, the Omics and Text-based Target Enrichment and Ranking (OTTER) method predicted ULK1 as a potential target of 13OD against NSCLC cells. This hypothesis was further confirmed using molecular docking, the cellular thermal shift assay (CETSA), and Western blot analysis. Remarkably, ULK1 siRNA inhibited 13OD's toxic activity in NSCLC cells. In line with these findings, 13OD was potent and non-toxic in the tumor xenograft model. Our findings suggested a possible mechanism for 13OD's role as a tumor suppressor and laid the groundwork for identifying targets for ingenane-type Diterpenoids.

Keywords

13-Oxyingenol-dodecanoate; Autophagy; Non-small cell lung cancer; ULK1.

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