Quercetin Inhibits Colorectal Cancer Cells Induced-Angiogenesis in Both Colorectal Cancer Cell and Endothelial Cell through Downregulation of VEGF-A/VEGFR2

Tamonwan Uttarawichien,Prasit Suwannalert,Nathawut Sibmooh,Witchuda Payuhakrit,Tasanee Inwisai,Chantra Kamnerdnond

doi:10.3390/scipharm89020023

Tamonwan Uttarawichien, Prasit Suwannalert + Show 4 more

Open Access

https://doi.org/10.3390/scipharm89020023

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Journal: Scientia Pharmaceutica	Publication Date: May 25, 2021
Citations: 4	License type: CC BY 4.0

Affiliation: Mahidol University, Ramathibodi Hospital

Abstract

Colorectal cancer (CRC) aggressiveness is caused by cancer angiogenesis which promotes the cancer growth and metastasis associated with poor prognosis and poor survival. The vascular endothelial growth factor-A (VEGF-A) and its receptor (VEGFR-2) form the major signaling pathway in cancer angiogenesis. This study aimed to investigate the anti-angiogenesis activity of quercetin in both colorectal cancer cells and endothelial cells. The tube formation of human vein endothelial cells (HUVECs) was determined by using conditioned media of HT-29 cells treated with quercetin co-cultured with HUVECs. The VEGF-A and NF-κB p65 protein expressions in the quercetin-treated HT-29 cells were determined by fluorescence assay and Western blot analysis. The VEGFR-2 protein expression in HUVECs was determined after they were co-cultured with the quercetin-treated HT-29 cells. Quercetin markedly decreased the HT-29 cell-induced angiogenesis in HUVECs. NF-κB p65 and VEGF-A protein expression were also inhibited by quercetin. Moreover, quercetin significantly inhibited VEGFR-2 expression and translocation in HUVECs after they were co-cultured with high dose quercetin-treated HT-29 cells. Taken together, quercetin had an anti-angiogenesis effect on VEGF-A inhibition related to the NF-κB signaling pathway in the HT-29 cells and reduced VEGFR-2 expression and translocation in HUVECs.

Highlights

Colorectal cancer (CRC) is currently the third most common cause of cancer mortality worldwide with more than 1.85 million cases and 850,000 deaths annually [1]
These results indicate that HT-29 cells have the capability to induce tube formation on human vein endothelial cells (HUVECs) while quercetin dramatically inhibits HT-29 cell-induced tube formation in a dose-dependent manner
Our findings showed the tube formation in HT-29 cell-induced HUVECs was markedly inhibited by quercetin in a dose-dependent manner, which indicates the anti-angiogenic activity of quercetin

Summary

Introduction

Colorectal cancer (CRC) is currently the third most common cause of cancer mortality worldwide with more than 1.85 million cases and 850,000 deaths annually [1]. CRC aggressiveness is caused by cancer angiogenesis, a type of neovascular formation which is essential for the normal physiological functions of tissues, such as wound healing and embryonic development, but which is an important factor in cancer progression due to cancer cells requiring it to provide them with proper nourishment and the removal of metabolic wastes, without which, cancer cells would die [5]. The expression of VEGF is increased by being induced both dependently and independently from hypoxia-inducible transcription factor (HIF) mechanisms through the activation of the NF-κB pathway in endothelial cells; when NF-κB is activated, it will translocate into the nucleus and up-regulate the angiogenic signals which are necessary for the vascularization process [12,13,14,15,16]. Their study showed that HIF-1α and VEGF were overexpressed in both the primary and matched metastatic tissues of the CRC. Inhibiting VEGF-A is needed for inhibiting both primary and metastatic CRC [17]

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