Key Takeaways & Executive Findings
- •• 2-DAIL exhibits significant anti-CRC activity in vitro and in vivo. • 2-DAIL directly binds to integrin alpha-3 (ITGA3) as revealed by SILAC-TPP. • 2-DAIL blocks the PI3K/AKT signaling pathway mediated by ITGA3 inhibition. • 2-DAIL is a promising drug candidate for CRC treatment and other ITGA3-related diseases.
Abstract
Colorectal cancer (CRC) remains a leading cause of cancer-related mortality, necessitating the discovery of novel therapeutic agents. Here, we report a natural small molecule, 2-dihydroailanthone (2-DAIL), as a promising candidate for CRC treatment. First, our results demonstrate that 2-DAIL exhibits significant anti-CRC activity in vitro and in vivo. Then, we find that 2-DAIL directly binds to integrin alpha-3 (ITGA3) revealed by stable isotope labeling by amino acids in cell culture coupled with thermal proteome profiling (SILAC-TPP). Additionally, the RNA sequencing data obtained from CRC cells and tumor tissues suggest that 2-DAIL blocks the PI3K/AKT signaling pathway mediated by ITGA3 inhibition. Collectively, 2-DAIL exerts its anti-CRC effects, at least partially, by binding to and inhibiting the function of ITGA3, thereby blocking the activation of the PI3K/AKT signaling pathway, which leads to CRC cell growth inhibition. Our study provides a promising drug candidate for the treatment of CRC and suggests the potential of 2-DAIL in treating other diseases linked to ITGA3 dysfunction.
1. Introduction
Colorectal cancer (CRC), one of the malignancies with the highest incidence and mortality rates globally, faces significant challenges in clinical management due to its complex pathogenesis and acquired chemoresistance [1,2]. Integrin receptors, as pivotal regulators of tumor cell-matrix interactions, orchestrate critical biological processes, including extracellular matrix signaling, transduction, and cytoskeletal remodeling, also playing a significant role in CRC [3,4]. Current integrin-targeted therapeutics in clinical development face substantial limitations, with most candidates remaining in early-stage clinical trials and exhibiting suboptimal therapeutic efficacy [5]. This therapeutic impasse underscores the urgent need for novel agents.
Terpenoids are a large family of plant-derived natural products characterized by a diverse array of unique chemical structures and prominent biological activities [6–8]. 2-Dihydroailanthone (2-DAIL), a terpenoid compound, first isolated from Ailanthus altissima (Mill.) Swingle exhibits excellent anti-tumor activity in vitro. However, current research on its role in CRC remains insufficient. Elucidating its therapeutic mechanisms in CRC holds significant importance for addressing current therapeutic challenges and advancing the development of lead compounds.
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Yunjie Hu, Congcong Li, Yongjiang Wang, Wei Wang, Li Huang, Haoran Lei, Sijuan Sun, Lilian Zhao, Yuanping Liu, Yuting Mu, Zhuohong Li, Hongbin Cheng, Yucheng Gu, Shengxiong Huang, Dong Wang, Dale Guo, Yun Deng (2026). Natural product 2-dihydroailanthone suppresses colorectal cancer via targeting integrin α3. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2026045
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Frequently Asked Questions
What is 2-dihydroailanthone (2-DAIL)?
2-DAIL is a natural terpenoid compound isolated from Ailanthus altissima (Mill.) Swingle. It exhibits anti-tumor activity and has been studied for its effects on colorectal cancer.
How does 2-DAIL suppress colorectal cancer?
2-DAIL directly binds to integrin alpha-3 (ITGA3), inhibiting its function and thereby blocking the PI3K/AKT signaling pathway, which leads to inhibition of CRC cell growth.
What is the significance of targeting ITGA3 in colorectal cancer?
ITGA3 is a pivotal regulator of tumor cell-matrix interactions and plays a significant role in CRC. Targeting ITGA3 with 2-DAIL provides a novel therapeutic approach for CRC treatment.
What methods were used to identify ITGA3 as the target of 2-DAIL?
The researchers used stable isotope labeling by amino acids in cell culture coupled with thermal proteome profiling (SILAC-TPP) to identify ITGA3 as a direct binding target of 2-DAIL.
What are the potential clinical implications of this study?
The study suggests that 2-DAIL is a promising drug candidate for CRC treatment and may also be effective in treating other diseases linked to ITGA3 dysfunction.
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