Abstract
Cholangiocarcinoma (CCA) is a malignant tumor with aggressive metastatic property resulted from dysregulation of metastasis-regulated signaling pathways. The aim of this study was to investigate the effect of cucurbitacin B on metastatic behavior of CCA cells through modulation of focal adhesion kinase (FAK) protein. KKU-452 cells were treated with a specific FAK inhibitor, FAK inhibitor-14, or cucurbitacin B at various concentrations for 24 h. Cell viability was assessed by sulforhodamine B assay. The migratory and invasive abilities of the cells were investigated using wound healing and transwell invasion assays, respectively. The fibronectin-coated plate was used for adhesion assay. The effects of the test compounds on FAK activation and the expression of metastasis-associated proteins were determined by Western blot analysis. The amount of MMP-9 was evaluated using a commercial ELISA Kit. FAK inhibitor-14 and cucurbitacin B at concentrations which minimally affected KKU-452 cell viability could suppress FAK activation, evidently by decreased level of phospho-FAK protein after exposure to the compound. At these conditions, cucurbitacin B suppressed metastatic behavior including migration, invasion and adhesion abilities of CCA cells similar to FAK inhibitor-14. Further molecular studies demonstrated that FAK inhibitor-14 and cucurbitacin B downregulated the expression of metastasis-associated proteins including MMP-9, ICAM-1 and VEGF. Consequently, exposure to cucurbitacin B inhibited the production of MMP-9 enzyme in CCA cells similar to FAK inhibitor-14 treatment. FAK participated in regulation of metastatic behavior of KKU-452 CCA cells. Cucurbitacin B suppressed FAK activation in the cells which was associated with inhibition of metastasis essential steps and their related metastatic proteins. The compound may be developed as a novel therapeutic agent for CCA metastasis therapy.<br />.
Highlights
Cholangiocarcinoma (CCA) or bile duct cancer is a malignant tumor with extremely aggressive metastatic behavior resulting in a very poor prognosis (Doherty et al, 2017)
Further molecular studies demonstrated that focal adhesion kinase (FAK) inhibitor-14 and cucurbitacin B downregulated the expression of metastasis-associated proteins including matrix metalloproteinase-9 (MMP-9), intercellular adhesion molecule-1 (ICAM-1) and vascular endothelial growth factor (VEGF)
Cucurbitacin B suppressed FAK activation in the cells which was associated with inhibition of metastasis essential steps and their related metastatic proteins
Summary
Cholangiocarcinoma (CCA) or bile duct cancer is a malignant tumor with extremely aggressive metastatic behavior resulting in a very poor prognosis (Doherty et al, 2017). Prognosis for patients with metastatic cancer is generally poor. The results showed that metastasis was a significant clinical predictor of death among these patients (Charonpongsuntorn et al, 2019). It is effective therapeutic compounds capable of suppressing CCA metastasis are still highly needed. Cancer cell metastasis depends on the ability of cells to migrate and invade in which they are influenced by the surrounding extracellular matrix (ECM) (Welch and Hurst, 2019). Besides migratory and invasive properties, Asian Pacific Journal of Cancer Prevention, Vol 22 219
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