Homoharringtonine Impedes Migration and Invasion by Inhibiting EphB4/SRI/EMT Signaling and Enhances the Antimetastatic Abilities of Erlotinib in Pancreatic Cancer.
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Abstract
Background: Homoharringtonine (HHT) is a purified alkaloid compound isolated from the plant Cephalotaxus, traditionally used in Chinese medicine for various ailments, including leukemia. However, the specific role and biological mechanisms by which HHT regulates metastasis in pancreatic cancer (PC) remain unclear. PC is notorious for its high metastatic potential, yet our understanding of the molecular mechanisms driving its metastasis is still limited. The primary aim of this study is to explore the antimetastatic potential of HHT in PC and elucidate its mechanism of inhibiting epithelial-mesenchymal transition (EMT) via EphB4 and SRI.
Materials and methods: Western blotting, RT-qPCR, immunofluorescence, and transfection of overexpression and shRNA vectors were employed to examine the expression levels of metastatic factors. Antimetastatic activities were evaluated using scratch and transwell assays. In vitro experiments were complemented by in vivo investigations, supported by immunohistochemistry.
Results: We identify a distinct molecular mechanism governing migration, invasion, and metastasis in PC through the EphB4/SRI/EMT pathway. Upregulation of EphB4 increased SRI expression, thereby promoting EMT-associated migration and invasion. A direct interaction between EphB4 and SRI facilitated EMT progression and cellular migration. HHT inhibited EphB4, leading to the downregulation of SRI and reversal of EMT-related markers (E-cadherin and N-cadherin). Moreover, HHT enhanced the antimetastatic effects of erlotinib (ERT) in both in vitro and in vivo PC models.
Discussion: The EphB4/SRI/EMT axis emerges as a novel regulatory pathway in PC metastasis, with EphB4 directly interacting with SRI to promote EMT and metastatic behavior. This discovery expands our understanding of the molecular networks driving PC progression, highlighting EphB4 and SRI as potential therapeutic targets. HHT, previously recognized for its antileukemic activity, is shown here to target this axis, reverse EMT, and reduce metastasis. Additionally, the synergistic effect of HHT with ERT suggests a promising combinatorial strategy to overcome the limitations of single-agent targeted therapy, particularly in addressing drug resistance in advanced PC.
Conclusion: HHT has been identified as an impediment to cell invasion and metastasis in PC via the EphB4/SRI/EMT axis. Additionally, HHT enhances the efficacy of ERT in inhibiting the migration of PC cells.
期刊介绍：
Current Cancer Drug Targets aims to cover all the latest and outstanding developments on the medicinal chemistry, pharmacology, molecular biology, genomics and biochemistry of contemporary molecular drug targets involved in cancer, e.g. disease specific proteins, receptors, enzymes and genes.
Current Cancer Drug Targets publishes original research articles, letters, reviews / mini-reviews, drug clinical trial studies and guest edited thematic issues written by leaders in the field covering a range of current topics on drug targets involved in cancer.
As the discovery, identification, characterization and validation of novel human drug targets for anti-cancer drug discovery continues to grow; this journal has become essential reading for all pharmaceutical scientists involved in drug discovery and development.
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