Isorhamnetin Induces Apoptosis and Suppresses Metastasis of Human Endometrial Carcinoma Ishikawa Cells via Endoplasmic Reticulum Stress Promotion and Matrix Metalloproteinase-2/9 Inhibition In Vitro and In Vivo

Abstract

Endometrial cancer (EC) is a very common female cancer which has attracted more and more attention. According to the individual patient’s condition, the current treatment of EC patients is mainly based on surgery, which is supplemented by chemotherapy, radiotherapy, and endocrine intervention. However, these existing treatment strategies also have some inevitable limitations. Therefore, it is particularly important to find an active ingredient with low toxicity and a high safety profile against EC. Isorhamnetin is a flavonoid known to be present in a variety of plants, such as sea buckthorn, dry willow, and wolfberry. In recent years, the anti-tumor effects of isorhamnetin have been reported. In our study, isorhamnetin was shown to induce apoptosis in Ishikawa cells by inducing the endogenous mitochondrial apoptotic pathway and exogenous death receptor pathway, promoting the endoplasmic reticulum stress-related pathway, and activating the corresponding markers of UPR response. In addition, isorhamnetin affected the expression of MMP2 and MMP9-related proteins in vitro and in vivo and eventually repressed metastasis. Therefore, isorhamnetin can be used as a promising medicinal material for the treatment of EC.

Independent organelle and organelle—organelle interactions: essential mechanisms for malignant gynecological cancer cell survival

“…Niclosamide (NIC) has emerged as a promising human endometrial cancer treatment by inducing Bax colocalization with lysosome and inhibiting Cathepsin B maturation from pro-cathepsin B, which induces lysosomal membrane permeability and releases hydrolase enzymes from the lysosome to cytosol, ultimately leading to cell death ( 122 ). Isorhamnetin is a flavonoid that affects ERS by modulating intracellular ROS levels, activating the endogenous mitochondrial apoptotic and exogenous death receptor pathways and ultimately inducing apoptosis, while inhibiting cell metastasis ( 123 ).…”

Identifying the Main Components and Mechanisms of Action of Artemisia annua L. in the Treatment of Endometrial Cancer Using Network Pharmacology

“… 44 Additionally, some studies have shown that kaempferol induces G2/M phase cell cycle arrest and apoptosis, inhibits cell invasion, and upregulates the m-TOR/PI3K signaling pathway, thus contributing to the suppression of endometrial cancer. 45 Furthermore, luteolin, 25 isorhamnetin, 46 artemetin, 25 and stigmasterol 47 have been found to inhibit the proliferation of endometrial cancer cells. Subsequently, we performed molecular docking of PTGS2 with quercetin, kaempferol, luteolin, isorhamnetin, artemetin, and stigmasterol and found that all of these components exhibited strong binding activity with PTGS2, with an affinity value smaller than −7.0 kcal/mol.…”

Construction of prognostic model and molecular subtypes based on endoplasmic reticulum stress-related lncRNAs in endometrial cancer

“…Researchers found that isorhamnetin exerted antitumor properties by activating the key proteins of mitochondria and ER-related pathways in EC cells [39]. Metformin inhibits the growth and survival of EC cells by inhibiting GRP78 and Wnt/β-catenin pathway [40].…”