Fraxetin down-regulates polo-like kinase 4 (PLK4) to inhibit proliferation, migration and invasion of prostate cancer cells through the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway

Abstract

Fraxetin, a natural product isolated from herb Cortex Fraxini , has been demonstrated to exhibit anti-cancer effects on various cancers. The aim of this work is to investigate the anti-tumor effect of Fraxetin in prostate cancer and the potential mechanisms. In this study, the prostatic epithelial cell RWPE-1 and prostate cancer cell DU145 were exposed to Fraxetin (10, 20, 40, and 80 μM) to detect the changes in cell viability using cell counting kit-8 (CCK-8) assay. Fraxetin (10, 20, and 40 μM) was utilized to treat DU145 cell, then the changes in cell proliferation, apoptosis, migration, and invasion were assessed. Western blot assay was employed to detect the expression of proteins that participate in the above cellular processes as well as Polo-like kinase 4 (PLK4), phosphatidylinositol 3-kinase (PI3K). In addition to 40 μM Fraxetin treatment, DU145 cells were overexpressed with PLK4, and then the above experiments were repeated. Results revealed that Fraxetin markedly decreased DU145 cell viability, but didn’t affect the cell viability of RWPE-1. Fraxetin suppressed cell proliferation, migration, invasion, and induced apoptosis of DU145 cells in a concentration-dependent manner. Furthermore, the expression of PLK4 and phosphorylated PI3K and protein kinase B (Akt) were reduced upon Fraxetin treatment. Finally, PLK4 overexpression significantly reversed all the effects of Fraxetin on DU145 cells. Collectively, Fraxetin acted as a cancer suppressor in prostate cancer through inhibiting PLK4 expression thereby inactivating PI3K/Akt signaling.

Fraxetin inhibits proliferation and induces apoptosis of bladder cancer through the Akt pathway in vitro and in vivo

“…Fraxetin acts as a cancer suppressor in prostate cancer via inhibiting PLK4 expression, thereby inactivating PI3K/Akt signaling. [ 13 ] Fraxetin inhibited proliferation, invasion, and migration and induced apoptosis of glioma by inhibiting JAK2/STAT3 signaling. [ 29 ] Fraxetin exhibited significant inhibitory effects on the proliferation and growth of lung cancer cells, and its mechanisms may be that fraxetin interacted with STAT3.…”

“…[ 10,11 ] Modern pharmacological studies have demonstrated the pharmacological properties of fraxetin, such as tumor suppression, inhibiting oxidative stress, immunomodulation effects, neuroprotection, antibacterial, and anti‐inflammatory. [ 12 ] Accumulating studies have confirmed the anticancer effects of fraxetin on various tumors, such as prostate cancer, [ 13 ] colon cancer, [ 14 ] glioma, [ 15 ] pancreatic cancer, [ 5 ] and lung cancer. [ 16 ] However, whether fraxetin exhibited an anticancer effect on bladder cancer remains unclear.…”

Assessing the Mechanism of Action of “Fructus Ligustri Lucidi-Cuscutae Semen” in Prostate Cancer Treatment Using Network Pharmacology and Molecular Docking

“…From a macroscopic perspective, the pathogenesis of PCa is related to factors such as advanced age, genetics, and prostatitis. From a microscopic perspective, genetic gene mutations such as BRCA1/2 and ESR1, activation of signalling pathways such as PI3K-AKT, and expression of the androgen receptor (AR) are potential pathogenic mechanisms leading to the proliferation and migration of PCa cells [ 6 , 10 , 11 ]. Studies have shown that both Fructus Ligustri Lucidi and Cuscutae Semen can enhance body immunity.…”

“…Potential active ingredient. Computational and Mathematical Methods in Medicine such as BRCA1/2 and ESR1, activation of signalling pathways such as PI3K-AKT, and expression of the androgen receptor (AR) are potential pathogenic mechanisms leading to the proliferation and migration of PCa cells[6,10,11].…”

Network pharmacology and molecular docking to elucidate the mechanism of pulsatilla decoction in the treatment of colon cancer

“…Fraxetin, the chemical component of Cortex Fraxini, has been shown to inhibit prostate cancer. Its chemical composition escin can inhibit the effects of ovarian and colorectal cancer ( Wang et al, 2018a ; Kenny et al, 2021 ; Ma et al, 2022 ).…”