The impact of Icariside II on human prostate cancer cell proliferation, mobility, and autophagy via PI3K-AKT-mTOR signaling pathway

Abstract

Background The flavonol glycoside icariside Ⅱ (ICA II) has been shown to exhibit a range of anti-tumor properties. Herein we evaluated the impact of ICA II on the proliferation, motility, and autophagy activity of human prostate cancer cells, and we further evaluated the molecular mechanisms underlying these effects. Methods Herein, we treated DU145 human prostate cancer cells with a range of ICA II doses. We then evaluated the proliferative abilities of these cells via CCK-8 assay, whereas apoptosis and cell cycle status were assessed via flow cytometry. We further utilized wound healing and transwell assays to probe the impact of ICA II on migratory and invasive activities, while autophagy was assessed via laser confocal fluorescence microscopy. Western blotting was further utilized to measure LC3-II/I, Beclin-1, P70S6K, PI3K, AKT, mTOR, phospho-AKT, phospho-mTOR, and phospho-P70S6K levels, with RT-PCR being used to evaluate the expression of these same genes at the mRNA level. Results We found that ICA II was capable of mediating a dose- and time-dependent suppression of prostate cancer cell proliferative activity, while also causing these cells to enter a state of cell cycle arrest and apoptosis. We further determined that ICA II treatment was associated with significant impairment of prostate cancer cell migratory and invasive abilities, whereas autophagy was enhanced in treated cells relative to untreated controls. Levels of p-P70S6K, p-mTOR, p-AKT, and PI3K were all also decreased by ICA II. Conclusion Our results indicate that ICA II treatment is capable of suppressing human prostate tumor cell proliferation and disrupting migratory activity while enhancing autophagy through PI3K-AKT-mTOR signaling. As such, ICA II may be an ideal candidate drug for the treatment of prostate cancer.

Icariside II enhances cisplatin-induced apoptosis by promoting endoplasmic reticulum stress signalling in non-small cell lung cancer cells

“…Several limitations exist in this study. First, IS has been proven to inhibit cancer cell growth by decreasing proliferation, invasion, migration and other mechanisms [34][35]. We tested the effects of IS on proliferation and then focused on apoptosis but did not perform experiments to assess invasion or migration, which remains to be studied.…”

Icariside II: Anticancer Potential and Molecular Targets in Solid Cancers

“…In human esophageal squamous carcinoma Eca109 cells, Icariside II was demonstrated to be highly effective in downregulating β-catenin and cyclin D1 protein expression and stochastically inducing cell cycle arrest ( Wang et al, 2011 ). The cell cycle blockage in human PC-3 and DU145 prostate cancer cells at the G0/G1 checkpoint was caused by Icariside II in a dose-dependent manner, which increased the percentage of cells undergoing G1 phase cell cycle arrest to 45.7–80% upon treatment with 40 µM ( Lee et al, 2009 ; Li et al, 2020 ). These results were supported in a study by Wei Z, which showed that Icariside II induced significant accumulation of cells at the G1/G0 phase with decreased cell populations at the S phase and the G2/M phase in cervical cancer (Sun et al, 2020).…”

“…Icariside II, as a novel phosphodiesterase 5 inhibitor, was found to play a role in regulating autophagy via the PI3K/AKT/mTOR, ROS/GSK-3β/mitochondrial, and PKG/GSK-3β signaling pathways in different diseases ( Gao et al, 2017 ; Gao et al, 2020 ; Li et al, 2020 ; Zhang et al, 2020 ). In human prostate cancer, autophagy induced by Icariside II was characterized by enhanced autophagosome formation, reduction in P70S6K expression, and upregulation of LC3 and Beclin-1 by inhibiting PI3K-AKT-mTOR activity ( Li et al, 2020 ). Till date, the influence of Icariside II on autophagy in different cancer cell lines is not well elucidated and more studies are needed to shed better light on this subject.…”

“…Accumulating evidence is indicating that Icariside II has the ability to control cancer cell invasion and migration in lung cancer ( Song et al, 2017 ), hepatocellular carcinoma ( Guo et al, 2020a ), cervical cancer ( Sun et al, 2020b ), osteosarcoma ( Choi et al, 2008 ), melanoma ( Peng and Zhang, 2018 ), and prostate cancer ( Li et al, 2020 ). In hepatocellular carcinoma ( Guo et al, 2020b ) and cervical cancer ( Sun et al, 2020a ), it has been demonstrated that Icariside II could weaken the migratory and invasive ability of HuH-7, HepG2, and HeLa cells through inhibiting metastasis-related protein MMP2/9 expression.…”

Pharmacological mechanism and therapeutic efficacy of Icariside II in the treatment of acute ischemic stroke: a systematic review and network pharmacological analysis

“…Herba Epimedii (commonly named as Yin-yang-huo in China) is a traditional herb or health food that is widely used in China for the prevention and treatment of various diseases. In vivo and in vitro studies have been conducted over the past few decades and found that ICS II can treat a variety of cancers including acute myeloid leukemia [15], prostate cancer [16], cervical cancer [17], etc. It has also been used to treat myocardial ischemic and reperfusion injury [18,19], ED [20,21] and many neurological disorders such as Alzheimer's disease [22][23][24], vascular dementia [25], and subarachnoid hemorrhage [26].…”