Hexameric procyanidins inhibit colorectal cancer cell growth through both redox and non-redox regulation of the epidermal growth factor signaling pathway

• Published in: Redox biology Vol. 38; p. 101830
• Main Authors: Daveri, Elena, Adamo, Ana M., Alfine, Eugenia, Zhu, Wei, Oteiza, Patricia I.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2021; Elsevier
• Subjects: Caco-2 Cells; Cell Line, Tumor; Colorectal cancer; Colorectal Neoplasms - drug therapy; Epidermal Growth Factor - metabolism; Epidermal growth factor receptor; ErbB Receptors; Humans; NADPH oxidase; Oxidation-Reduction; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Proanthocyanidins; Proanthocyanidins - pharmacology; Redox regulation; Research Paper; Signal Transduction; NADPH oxidase; Epidermal growth factor receptor; Colorectal cancer; Redox regulation; Proanthocyanidins
• ISSN: 2213-2317; 2213-2317
• DOI: 10.1016/j.redox.2020.101830

Dietary proanthocyanidins (PAC) consumption is associated with a decreased risk for colorectal cancer (CRC). Dysregulation of the epidermal growth factor (EGF) receptor (EGFR) signaling pathway is frequent in human cancers, including CRC. We previously showed that hexameric PAC (Hex) exert anti-proliferative and pro-apoptotic actions in human CRC cells. This work investigated if Hex could exert anti-CRC effects through its capacity to regulate the EGFR pathway. In proliferating Caco-2 cells, Hex acted attenuating EGF-induced EGFR dimerization and NADPH oxidase-dependent phosphorylation at Tyr 1068, decreasing EGFR location at lipid rafts, and inhibiting the downstream activation of pro-proliferative and anti-apoptotic pathways, i.e. Raf/MEK/ERK1/2 and PI3K/Akt. Hex also promoted EGFR internalization both in the absence and presence of EGF. While Hex decreased EGFR phosphorylation at Tyr 1068, it increased EGFR Tyr 1045 phosphorylation. The latter provides a docking site for the ubiquitin ligase c-Cbl and promotes EGFR degradation by lysosomes. Importantly, Hex acted synergistically with the EGFR-targeted chemotherapeutic drug Erlotinib, both in their capacity to decrease EGFR phosphorylation and inhibit cell growth. Thus, dietary PAC could exert anti-CRC actions by modulating, through both redox- and non-redox-regulated mechanisms, the EGFR pro-oncogenic signaling pathway. Additionally, Hex could also potentiate the actions of EGFR-targeted drugs. [Display omitted] •Hexameric (Hex) procyanidins inhibit colorectal cancer cell (CRC) growth.•Hex acts inhibiting the EGF receptor (EGFR) signaling pathway.•Hex inhibits the NADPH oxidase-regulated EGFR activation.•Hex inhibits receptor dimerization, promotes EGFR internalization and degradation.•Inhibition of the EGFR pathway mediate in part Hex effects on CRC cell growth.