Aryl hydrocarbon receptor-dependent apoptotic cell death induced by the flavonoid chrysin in human colorectal cancer cells

Abstract

The polyphenolic flavone chrysin has been evaluated as a natural chemopreventive agent due to its anti-cancer effects in a variety of cancer cell lines. However, the mechanism of the chemopreventive effect has been not well established, especially in human colorectal cancer cells. We evaluated the chemopreventive effect of chrysin in three different human colorectal cancer cell lines. We found that chrysin treatment consequently reduced cell viability via induction of apoptosis. We identified that the involvement of up-regulation of pro-apoptotic cytokines tumor necrosis factor (Tnf) α and β genes and consequent activation of the TNF-mediated transcriptional pathway in chrysin-induced apoptosis. Using our generated AHR siRNA expressing colorectal cancer cells, we demonstrated that the chrysin-induced up-regulation of Tnfα and β gene expression was dependent on the aryl hydrocarbon receptor (AHR), which is a ligand-receptor for chrysin. Subsequently, we found that the AHR siRNA expressing colorectal cancer cells were resistant to chrysin-induced apoptosis. Therefore, we concluded that AHR is required for the chrysin-induced apoptosis and the up-regulation of Tnfα and β gene expression in human colorectal cancer cells.

Indole-3-carbinol induces tumor cell death: function follows form

“…To our knowledge, our study represents the first time that colorectal cancer cell death by indole-3-carbinol has been even partially linked to AHR activation. Additionally, our group recently established that chrysin, another natural ligand of the AHR, induces apoptosis in human colon cancer cell cells in an AHR-dependent fashion (39). Together, these works represent an initial characterization of the AHR as a novel putative target in both chemoprevention as well as chemotherapy for colorectal cancer.…”

“…We have previously identified Tnf and c-fos activity as the means by which aryl hydrocarbon receptor activation by the flavonoid chrysin leads to apoptosis (39). Also, the aryl hydrocarbon receptor has been found to mediate raloxifene-induced apoptosis in triple-negative breast cancer cells and estrogen receptor-deficient hepatoma cells (43).…”

“…Generation of small interfering RNA (siRNA) stable expression cell lines on a HCT116 colon carcinoma background was conducted according to an established lab protocol as published elsewhere (39). Si-AHR lines exhibit approximately 60% knockdown of AHR signaling (39).…”

“…Si-AHR lines exhibit approximately 60% knockdown of AHR signaling (39). Si-Scramble lines stably express a scrambled siRNA transcript to act as a control to the Si-AHR lines.…”

Novel Aryl Hydrocarbon Receptor Agonist Suppresses Migration and Invasion of Breast Cancer Cells

“…Interestingly, some flavonoid compounds exert their effects through activation of Ahr [20, 21]. Unlike most of the known flavonoids, few studies have been performed to study the biological significance of Flavipin [22, 23].…”