Calycosin suppresses colorectal cancer progression by targeting ERβ, upregulating PTEN, and inhibiting PI3K/Akt signal pathway

Abstract

High intake of phytoestrogen has been reported to be associated with the prevention of colorectal cancer (CRC). Calycosin belongs to the phytoestrogen that has been shown to suppress CRC cells in our previous study. However, its anticancer activity and molecular mechanisms have not been elucidated. In this study, we analyzed the effect of calycosin on the viability and apoptosis of human CRC HCT116 and SW480 cells via MTT assay, flow cytometry assay, and caspase-3/7 activity assay. The protein expressions of estrogen receptor β (ERβ), PTEN, and PI3K/Akt signal pathways were determined by Western blot analysis. And then, the alterations of biological behavior in CRC cells transfected with ERβ siRNA were analyzed. Mouse xenograft models were further performed to detect the antitumor effect in vivo. The results show that calycosin reduces CRC cell viability, induces cell apoptosis, and suppresses xenograft tumor growth. The protein expressions of ERβ and PTEN are significantly upregulated following calycosin treatment, whereas p-AKT/AKT ratio and Bcl-2 level are downregulated. Suppressing ERβ with siRNA partially attenuates the reduction in viability and apoptosis induced by calycosin. Our results indicate that calycosin shows inhibitory effects on CRC cells, which might be obtained by targeting ERβ, upregulating PTEN, and inhibiting the PI3K/Akt signal pathway.

Isoliquiritigenin Inhibits the Growth of Colorectal Cancer Cells through the ESR2/PI3K/AKT Signalling Pathway

“…In addition, the anti-tumour effect of ISL, as a typical phytoestrogen, has been found to be related to oestrogen receptors [ 26 , 27 , 28 ]. It has been found that oestrogen receptors can participate in tumour growth and metastasis by regulating the PI3K signalling pathway [ 29 ]. ESR2 (oestrogen receptor beta), PIK3CG (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma) and GSK3β (glycogen synthase kinase three beta), the predicted common drug–disease targets, are typical targets involved in the oestrogen signalling pathway and the PI3K/AKT pathway.…”

Unveiling the potential anti‐cancer activity of calycosin against multivarious cancers with molecular insights: A promising frontier in cancer research

“…Lin Zu demonstrated that calycosin could suppress the growth of xenograft mouse tumors by inhibiting the PI3K/Akt signaling pathway and increasing ER-β using siRNA and PTEN. 68 Another study led by Zhao X. showed that ERβ, a mediator of the stimulation of ER-alpha, IGF-1R, p-Akt, and miR-95 expression, can suppress the proliferation of CRC cells caused by calycosin (0-80 μM) in both in vitro and in vivo model. 69 Chen J. et al declared their finding calycosin (0-100 μM) reduced cell proliferation, induced apoptosis, and upregulated of PTEN due to an elevation in ER-β as evaluated by MMT assay, flow cytometry, transwell invasion test, and mRNA levels by rt-PCR.…”

“…Calycosin has been proven via a number of studies to slow the progression of colorectal cancer cell. Lin Zu demonstrated that calycosin could suppress the growth of xenograft mouse tumors by inhibiting the PI3K/Akt signaling pathway and increasing ER‐β using siRNA and PTEN 68 . Another study led by Zhao X. showed that ER‐β, a mediator of the stimulation of ER‐alpha, IGF‐1R, p‐Akt, and miR‐95 expression, can suppress the proliferation of CRC cells caused by calycosin (0–80 M) in both in vitro and in vivo model 69 .…”

ER‐α36 is involved in calycosin inhibition of IL‐6 production in macrophages

“…20 Calycosin, a major isoflavonoid in Radix Astragali, exhibits potent anti-inflammatory and antioxidant properties. 21 In addition, calycosin exhibits various anticancer properties [22][23][24] ; its mechanism of action, however, is not well understood.…”