Abstract
Sulfated galactans (SG) isolated from red alga Gracilaria fisheri have been reported to inhibit the growth of cholangiocarcinoma (CCA) cells, which was similar to the epidermal growth factor receptor (EGFR)-targeted drug, cetuximab. Herein, we studied the anti-cancer potency of SG compared to cetuximab. Biological studies demonstrated SG and cetuximab had similar inhibition mechanisms in CCA cells by down-regulating EGFR/ERK pathway, and the combined treatment induced a greater inhibition effect. The molecular docking study revealed that SG binds to the dimerization domain of EGFR, and this was confirmed by dimerization assay, which showed that SG inhibited ligand-induced EGFR dimer formation. Synchrotron FTIR microspectroscopy was employed to examine alterations in cellular macromolecules after drug treatment. The SR-FTIR-MS elicited similar spectral signatures of SG and cetuximab, pointing towards the bands of RNA/DNA, lipids, and amide I vibrations, which were inconsistent with the changes of signaling proteins in CCA cells after drug treatment. Thus, this study demonstrates the underlined anti-cancer mechanism of SG by interfering with EGFR dimerization. In addition, we reveal that FTIR signature spectra offer a useful tool for screening anti-cancer drugs’ effect.
Highlights
Cholangiocarcinoma (CCA) is a malignant cancer of the bile duct epithelium
The results demonstrated that HuCCA-1 cells treated with either cetuximab or Sulfated galactans (SG) alone showed a reduction in p-epidermal growth factor receptor (EGFR)/EGFR (Figure 3A), p-ERK1/2/ERK1/2 (Figure 3B), and p-focal adhesion kinase (FAK)/FAK (Figure 3C) but increased the expression of E-cadherin (Figure 3D)
EGFR signaling has been shown to regulate different processes involved in tumor development, such as proliferation [20], migration and invasion [21]
Summary
Cholangiocarcinoma (CCA) is a malignant cancer of the bile duct epithelium. The largest incidence of CCA has been reported in the northeast part of Thailand (135.4 per100,000) [1], where development of CCA has been shown to correlate with liver fluke (Opistorchis viverrini) infection. Cholangiocarcinoma (CCA) is a malignant cancer of the bile duct epithelium. The largest incidence of CCA has been reported in the northeast part of Thailand 100,000) [1], where development of CCA has been shown to correlate with liver fluke (Opistorchis viverrini) infection. There are no efficient tools for early detection and no effective treatment strategies for CCA patients [2,3]. The epidermal growth factor receptor (EGFR) is a tyrosine kinase receptor and is overexpressed in many tumor cell types, including CCA. EGFR is one of the most common and promising target proteins in anti-cancer therapy. The epidermal growth factor (EGF) is a ligand that activates EGFR by binding to the EGFR extracellular domains
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