Anti-metastatic Potential of Natural Triterpenoid Cucurbitacin B Against Cholangiocarcinoma Cells by Targeting Src Protein

Abstract

Owing to the crucial role of Src in cancer metastasis, interruption of Src and its signaling has been considered a promising strategy for cancer metastasis treatment. Cucurbitacin B, a dietary triterpenoid, has been shown to possess anti-proliferative and apoptosis-inducing activities in cholangiocarcinoma (CCA) cells via suppressing the activation of FAK which is a main downstream Src effector. We hypothesized that cucurbitacin B might act as a Src suppressant which conferring anti-metastasis effect against CCA cells. To investigate this, the role of Src in regulating metastasis behavior of CCA cells and the effect of cucurbitacin B on Src-mediated metastatic phenotype of these cells were determined. The results showed that activation of Src significantly enhanced the migratory and invasive abilities of CCA cells. Molecular analysis revealed that Src-facilitated metastasis behavior of CCA cells occurred by modifying expression of a wide range of metastasis-related genes in the cells. Consistent with gene expression results, activation of Src significantly induced the protein expression of 2 important metastasis-associated molecules, MMP-9 and VEGF. Cucurbitacin B markedly suppressed activation of Src and its key effector, FAK. As a consequence, the alteration of expression profiles of metastasis-associated genes induced by Src activator in CCA cells was diminished by cucurbitacin B treatment. The compound also down-regulated Src-induced expression of MMP-9 and VEGF proteins in the cells. Moreover, molecular docking analysis revealed that cucurbitacin B could interact with Src kinase domain and possibly restrain the kinase from being activated by hindering the ATP binding. In conclusion, cucurbitacin B exhibited anti-metastatic property in CCA cells via negatively influencing Src and Src-related oncogenic signaling. This compound may therefore be a potential therapeutic drug for further development as an anti-Src agent for treatment of metastatic CCA.

Depolymerization of actin filaments by Cucurbitacin I through binding G‐actin

“…shown that CuB has anti-migration ability in cancer cell lines (Huifu et al, 2023;Kaewmeesri et al, 2022). Although anti-migration activity seems to be due to inhibition of STAT3 and enhancement of STAT1 signaling, our results suggest that the reason could be binding G-actin (Guo et al, 2018).…”

“…Besides, the F‐actin polymerization rate was analyzed and compared with the other actin‐binding drugs, jasplakinolide and cytochalasin D, and it has been realized that CuI (200 nM) reduced the polymerization rate of F‐actin nearly as much as jasplakinolide and cytochalasin D. In our study, the formation of large cytoplasmic actin aggregates was observed in HUVECs by fluorescence microscopy, similar to Kenecht's study (Knecht et al., 2010 ). Recent studies have shown that CuB has anti‐migration ability in cancer cell lines (Huifu et al., 2023 ; Kaewmeesri et al., 2022 ). Although anti‐migration activity seems to be due to inhibition of STAT3 and enhancement of STAT1 signaling, our results suggest that the reason could be binding G‐actin (Guo et al., 2018 ).…”

Naturally Occurring Rhamnopyranosides as Anticancer Agents: Molecular Docking and ADMET Study

“…It can be used at many stages of the drug design process to: (i) anticipate the binding mode of already known ligands; (ii) find novel and potent ligands; and (iii) as a tool to forecast binding affinity [46,47]. In our study, we used molecular docking of compounds 3-6 employing freely available PyRx (AutoDock) software [48,49].…”

Neuroprotective potential of formononetin, a naturally occurring isoflavone phytoestrogen

“…Open Babel and Autodock‐vina wizard and Python in‐built in PyRx software, whereas Open Babel is used for energy minimization of active ligand molecules and Vina wizard is used to perform docking of selected prepared molecules. Molecular docking analysis was visualized by Pymol and 2D and 3D interaction was examined using Pymol software (Kaewmeesri et al, 2022).…”