EGFR Inhibition by Curcumin in Cancer Cells: A Dual Mode of Action

Abstract

Epidermal Growth Factor Receptor (EGFR) is an important target of anticancer therapy. Nowadays, the search for new molecules inhibiting this receptor is turning toward natural substances. One of the most promising natural compounds that have shown an anti-EGFR activity is curcumin, a polyphenol found in turmeric. Its effect on the receptor kinase activity and on the receptor autophosphorylation has been already described, but the mechanism of how curcumin interacts with EGFR is not fully elucidated. We demonstrate that the mode of action of curcumin is dual. This polyphenol is able to inhibit directly but partially the enzymatic activity of the EGFR intracellular domain. The present work shows that curcumin also influences the cell membrane environment of EGFR. Using biomimetic membrane models, we show that curcumin insertion into the lipid bilayer leads to its rigidification. Single particle tracking analyses performed in the membrane of A431 cancer cells confirmed that this effect of curcumin on the membrane slows down the receptor diffusion. This is likely to affect the receptor dimerization and, in turn, its activation.

Spices for Prevention and Treatment of Cancers

“…Mitochondrial membrane potential was decreased, the release of cytochrome c into the cytosol was induced, and then caspase-9 and caspase-3 were activated [34]. Besides, curcumin inhibited the enzymatic activity of the epidermal growth factor receptor (EGFR) intracellular domain, and also influenced the cell membrane environment of EGFR, which was involved in the growth of lung cancer [35]. According to another study, the crosstalk between adherens’ junctions and Wnt signaling pathways was regulated by early growth response 1 (EGR-1), suggesting that EGR-1 might regulate cell proliferation and migration, which was confirmed in vitro.…”

Curcumin sensitized the antitumour effects of irradiation in promoting apoptosis of oesophageal squamous-cell carcinoma through NF-κB signalling pathway

“…Likewise, Zhu et al [39] reported that curcumin suppressed lung cancer stem cells via inhibiting Wnt/beta-catenin and sonic hedgehog pathways. Intriguingly, a recent study presented by Starok et al [40] demonstrated that insertion of curcumin into lipid bilayer influenced the cell membrane environment and interfered with EGFR signalling as well. Curcumin has also been revealed with promising results against the glioblastoma multiforme while in combination with cytotoxic chemotherapy agents.…”

“…reported that curcumin suppressed lung cancer stem cells via inhibiting Wnt/beta‐catenin and sonic hedgehog pathways. Intriguingly, a recent study presented by Starok et al . demonstrated that insertion of curcumin into lipid bilayer influenced the cell membrane environment and interfered with EGFR signalling as well.…”

Unraveling the Anticancer Effect of Curcumin and Resveratrol

“…The structure of EGF receptor is represented by an extracellular ligand-binding domain, a single transmembrane region with hydrophobic characteristics, and an intracellular module including the tyrosine kinase domain [75]. …”

“…Curcumin was able to inhibit EGFR tyrosine kinase in a concentration of 1 μM after 4 h of cell exposoure. The exact molecular mechanism of this short-term inhibition remains unknown [75]. …”