Department of Anorectal Branch, China Academy of Chinese Medical Sciences, Beijing, China.
Department of Surgery, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
Bioengineered. 2021 Dec;12(2):12940-12953. doi: 10.1080/21655979.2021.2012626.
Homoharringtonine (HHT), an Food and Drug Administration (FDA)-approved anti-leukemia drug, exerts anti-tumor activity in several solid tumors, including colorectal cancer (CRC). However, its mechanism of action in CRC progression has not been comprehensively elucidated. The drug-disease targets were obtained using publicly available databases. Protein-protein interaction (PPI) network, Gene ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were performed to reveal the core targets, biological processes and signaling pathways of HHT against CRC. Cell and animal experiments were performed to validate the inhibitory effects of HHT on CRC. A total of 98 overlapping target genes of HHT and CRC were predicted. Through PPI network and topology analysis, we screened out 23 hub genes. Enrichment assays showed 163 biological processes (BP), 18 cell components (CC), 35 molecular functions (MF), and 85 related pathways. Functionally, HHT inhibited CRC cell proliferation, cell cycle progression, colony formation, migration and invasion, and promoted apoptosis. HHT treatment resulted in the inactivation of PI3K/AKT/mTOR signaling in CRC cells. Moreover, activation of PI3K/AKT/mTOR signaling by 740Y-P abated the suppressive effects of HHT on cell malignant phenotypes. Furthermore, HHT repressed CRC tumor growth in nude mice. Our current study demonstrated that HHT repressed CRC progression at least partly by inactivating PI3K/AKT/mTOR signaling pathways, highlighting HHT as a potential therapeutic agent for CRC patients.
高三尖杉酯碱（HHT）是一种获得美国食品药品监督管理局（FDA）批准的抗白血病药物，对包括结直肠癌（CRC）在内的几种实体瘤具有抗肿瘤活性。然而，其在 CRC 进展中的作用机制尚未得到全面阐明。使用公开可用的数据库获得药物-疾病靶点。进行蛋白质-蛋白质相互作用（PPI）网络、基因本体论（GO）功能和京都基因与基因组百科全书（KEGG）通路富集分析，以揭示 HHT 针对 CRC 的核心靶点、生物学过程和信号通路。进行细胞和动物实验以验证 HHT 对 CRC 的抑制作用。共预测了 HHT 和 CRC 的 98 个重叠靶基因。通过 PPI 网络和拓扑分析，筛选出 23 个关键基因。富集分析显示了 163 个生物学过程（BP）、18 个细胞成分（CC）、35 个分子功能（MF）和 85 个相关通路。功能上，HHT 抑制 CRC 细胞增殖、细胞周期进程、集落形成、迁移和侵袭，并促进细胞凋亡。HHT 处理导致 CRC 细胞中 PI3K/AKT/mTOR 信号失活。此外，740Y-P 激活 PI3K/AKT/mTOR 信号减弱了 HHT 对细胞恶性表型的抑制作用。此外，HHT 抑制了裸鼠 CRC 肿瘤的生长。本研究表明，HHT 通过抑制 PI3K/AKT/mTOR 信号通路至少部分抑制 CRC 进展，凸显了 HHT 作为 CRC 患者潜在治疗药物的潜力。
